Blood pressure control in practice

Interview with G. Mancia, Italy

Giuseppe MANCIA, MD, PhD
Centro Interuniversitario di
Fisiologia Clinica e Ipertensione
Milan, ITALY

What are the key factors influencing blood pressure control in clinical practice?

Several factors are known to present a barrier in the hypertensive population to blood pressure control, which is notoriously low worldwide. They can be grouped into four major categories: (i) deficiencies of health-care systems, which are especially prominent in the area of cardiovascular prevention; (ii) physician inertia, ie, the fact that many physicians fail to modify treatment when, at a given visit, they see the blood pressure of the patient to be above control values; (iii) physicians’ unawareness or unwillingness to give preference to antihypertensive treatment strategies that have been shown to effectively control blood pressure, such as the combination of two or more drugs rather than monotherapy; and (iv) poor adherence to the prescribed treatment, a devastating phenomenon that is probably the number one reason for the poor blood pressure control in hypertensive individuals.

Poor adherence to treatment is an important factor leading to low rates of blood pressure control identified by the most recent 2013 European hypertension guidelines. What measures can be taken to improve patients’ confidence in their treatment and thus improve adherence?

The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines emphasize the importance of poor adherence to antihypertensive treatment as perhaps the main cause of poor blood pressure control in the hypertensive population.1 Since their publication, the perception has grown that this is perhaps the main barrier to overcome in order to improve the number of patients with blood pressure control. The number of studies devoted to how to measure adherence, determine which factors favor or oppose it, and examine the relationship adherence has with the risk of cardiovascular events and mortality has grown alongside. Thanks to these studies, we know that adherence is an extremely complicated phenomenon because: (i) there are many different nonadherence patterns; and (ii) no patient can be defined “tout court” as adherent or nonadherent.

Patients can be fully adherent to a prescribed treatment regimen over a given fraction of their life and not adherent at all at other times. Factors involved in adherence to treatment are multiple and interactive. In our analysis of the Lombardy database (10 million residents in the region), we saw that adherence to antihypertensive treatment was favorably affected by some cotreatments (eg, antidiabetic drugs), presumably because having diabetes improves the perception of the importance of blood pressure control.

It was also, perhaps for the same reason, favorably affected by previous hospitalization for cardiovascular or renal disease. It was, on the other hand, worse in patients previously hospitalized for lung disease, rheumatic disease, or cancer, in all likelihood because this removed concern and attention from blood pressure control to other medical problems. There was also somewhat unexpected evidence that adherence was related to the density of the population in the geographical area where the patients lived. That is, patients in metropolitan areas had worse adherence to treatment overall than patients living in smaller towns or rural areas. We figured that, in the latter instance, it was probably related to the fact that it is easier in rural areas to see a doctor and establish an effective relationship with him/her.

Finally, there was a major relationship between adherence to treatment and the class or type of antihypertensive drug(s) prescribed; adherence being highest with blockers of the renin-angiotensin system (RAS) and lowest with diuretics and β-blockers, and better with treatments based on drug combinations (particularly in single-tablet form) versus monotherapies. Data very clearly indicated that adherence to treatment was related to patient protection, ie, the lower the adherence, the higher the risk of outcomes and death. This has now been documented by many studies, and overall the relationship between adherence and outcomes appears to be so strong that even a modest improvement in adherence would be highly beneficial for public health.

How can adherence be improved?

Many steps are potentially useful, and some have been tested with reasonably good results. It is well known that adherence can be improved by: (i) using drugs with a good tolerability profile because side effects are a major cause of treatment discontinuation; (ii) privileging the use of combination treatment because of its association with better blood pressure control, which reassures patients and encourages them to continue treatment; and (iii) using simple treatment strategies. Single-tablet combinations, for example, have been repeatedly shown to improve adherence to treatment with respect to free combinations and, as a consequence, single-tablet combinations favor blood pressure control.

It is also well known that other measures can have favorable effects: better awareness of the protective effect of treatment by the patient, involvement of close relatives in the treatment schedule, and self-measurement of blood pressure at home. There are also hopes for the future that electronic devices and interventions, such as telemetry (which improves physicians’ feedback on patients’ needs and queries) and sound alerts on mobile phones, etc, may have a real impact on adherence, although studies on their usefulness are still at an initial phase. It should, in this context, be emphasized that studying the effects of a given measure of adherence to treatment is by no means easy. Most current measures of adherence are indirect and inaccurate. The few direct measures available are difficult to apply in a continuous fashion (multiple assessments over time), which is needed to cope with the dynamic nature of adherence. In addition, studies must be done under conditions that are pertinent to real life. Studying adherence in clinical trials has limited value because recruitment alters patients’ behavior (the so-called Hawthorne effect).

Physician inertia has also been identified by the most recent 2013 European hypertension guidelines as a key factor impacting blood pressure control. How can the use of combination treatment from diagnosis reduce this inertia?

As I mentioned before, this is another important barrier to blood pressure control. Several studies have shown that in real-life medicine, a large number of physicians fail to take action when they see that a patient has blood pressure values above the recommended target. Interestingly, adoption of a wait-and-see attitude rather than one of upgrading treatment when blood pressure is still high has also been shown in trials, ie, where physicians are required to control blood pressure by upgrading treatment according to a predetermined algorithm. The result can be highly damaging because blood pressure values measured at any given visit have an independent predictive value for outcome.

By analyzing data from INVEST (INternational VErapamil-SR/ trandolapril STudy),2 which included about 23 000 hypertensive patients with coronary disease, we found that for any given on-treatment average blood pressure, cardiovascular risk was progressively lower as the number of visits with blood pressure control increased. Improvement may have come from a better awareness by the doctor of the benefits of blood pres- sure control. It may also have come from making patients more demanding via self-measurement of blood pressure. It may finally have come from greater use of initial combination treatment, which bypasses physicians’ reluctance to add further drugs to initial monotherapy.

In practice, what are the benefits of initiating combination treatment in patients as soon as hypertension is diagnosed?

No randomized trial has looked at whether starting treatment with two drugs reduces cardiovascular events more than starting treatment with one drug and moving to combination treatment (whenever needed) later. Support comes, however, from many observational studies that suggest that the prompter blood pressure control that can be obtained by the initial use of two antihypertensive drugs may have several advantages over the delayed control that often accompanies initial monotherapy and combination treatment at a later time only.

First, in a post hoc analysis of the hypertensive patients with high cardiovascular risk of VALUE (Valsartan Antihypertensive Long-term Use Evaluation), prompt blood pressure control (ie, control within one month) was associated with a lower risk of outcomes compared to later control.3 Second, prompt blood pressure control shortens the titration phase, reduces the number of visits (and thus initial treatment costs), and attenuates the therapeutic inertia phenomenon. Third, recent large scale studies have shown that starting treatment with drug combinations is accompanied by less treatment discontinuation; this being the case both when combinations including a diuretic are compared with diuretic monotherapy, and when combinations without a diuretic are compared with monotherapies other than a diuretic. This is probably the factor predominantly responsible for the fact that patients on initial combination treatment have a much greater chance of having their blood pressure controlled in the long term, ie, after one or two years.

Fourth, better long-term adherence to treatment and blood pressure control are probably also responsible for the evidence from two observational studies that initial combination treatment is associated with greater cardiovascular protection. One of these studies was based on the large number of patients in the Lombardy database. There was 26% less hospitalization for coronary and cerebrovascular events in patients in whom treatment was started and continued with a drug combination than in those who started treatment with a single drug and moved to a combination later.

What are the potential problems, in practice, of initiating a combination treatment in patients from the diagnosis of hypertension, and how can these be overcome?
The 2013 ESH/ESC hypertension guidelines mention problems related to initial combination treatment,1 namely: (i) in patients in whom blood pressure could be controlled by monotherapy one unnecessary drug is prescribed; (ii) two drugs prescribed together make attribution of drug dependent side effects more difficult; and (iii) if single tablet combinations are used, titration to blood pressure control may be less flexible, ie, increasing dose involves two drugs simultaneously, rather than one drug at a time.

However, these problems are more theoretical than real because the number of patients in whom blood pressure can be controlled by one drug only is small, particularly if elevated blood pressure is in the moderate or severe range. The tolerability profile of most combinations is by no means worse (indeed, it can be better) than that of single drugs. Furthermore, many single-tablet combinations are now available in a variety of different dosages of the combination components, which makes up- or downtitration of treatment almost as flexible as if drugs were used in free combination form.

What are the ideal antihypertensive drug classes to combine when initiating combination treatment?

According to the 2013 ESH/ESC guidelines,1 many combinations can be used and certain ones may be preferred in special clinical circumstances. In fact, the only combination that is not recommended is that of an angiotensin- converting enzyme (ACE) inhibitor and an angiotensin receptor antagonist (or a renin inhibitor with one or the other drug class) because of serious shortcomings observed in clinical trials. At the other end of the spectrum, some priorityuse combinations have also been identified, ie, a RAS blocker with a calcium channel blocker, a RAS blocker with a diuretic (hydrochlorothiazide, indapamide, or chlorthalidone), and a diuretic with a calcium channel blocker. Both ACE inhibitors and angiotensin receptor antagonists are considered suitable RAS blockers, ACE inhibitors having the advantage of more widespread use in outcome trials, including the best trial so far performed for combination treatment comparisons, ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension).4

Interestingly, although ACCOMPLISH found the ACE inhibitor/ calcium channel blocker combination to be more protective than the ACE inhibitor/hydrochlorothiazide combination, the European guidelines consider both combinations of equal worth because in trials comparing initially administered calcium channel blockers and diuretics, no superiority of one drug versus the other has usually been found. Choice may be guided by the clinical characteristics of the patient. For example, a diuretic-based combination may be more appropriate in patients with hypervolemia whereas a calcium antagonist–based combination may be more appropriate in patients with metabolic abnormalities, which may be worsened by diuretics.

Is there evidence to support the use of combination therapy as initial treatment, from diagnosis, in grade 1 hypertension?

Doctors should consider initial combination treatment in patients at high cardiovascular risk, which means patients with blood pressures clearly above 140/90 mm Hg (grade 2 or 3 hypertension), according to the 2013 European hypertension guidelines.1 This should also, however, include patients with more modest blood pressure elevation (grade 1 hypertension), provided their cardiovascular risk is high because of diabetes, cardiovascular disease, renal disease, or advanced organ damage. This is largely based on “common sense” considerations, namely the fact that in high cardiovascular risk individuals an event can occur within a short time, so achieving prompt blood pressure control is a highly desirable goal.

Based on recent evidence, however, prompter blood pressure control associated with the use of initial combination treatment may also offer advantages in patients with grade 1 hypertension and low-to-moderate cardiovascular risk. Long-term advantages of initial combination treatment (improved adherence, reduced therapeutic inertia, and reduced cardiovascular events) have been reported for general hypertensive populations, ie, populations largely including grade 1 hypertension. At variance with previous reports, recent meta-analyses show that in these patients antihypertensive treatment is accompanied by clear-cut cardiovascular protection. Finally, in the recently published HOPE-3 (Heart Outcomes Prevention Evaluation 3) trial,5 initial combination treatment (a RAS blocker and a diuretic) was found to significantly reduce outcomes (-23%) in patients with grade 1 hypertension (systolic blood pressure >143 mm Hg, mean 154 mm Hg) and moderate cardiovascular risk.■

1. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159-2219.
2. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al; INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21): 2805-2816.
3. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet. 2004;363(9426):2049-2051.
4. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-2428.
5. Lonn EM, Bosch J, López-Jaramillo P, et al; HOPE-3 Investigators. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21):2009-2020.

Keywords: blood pressure control; hypertension guidelines; adherence; physician inertia; initial treatment; combination therapy; preferred combination