Blood pressure control – Slowly getting there through new strategies?

Blood pressure control – Slowly getting there through new strategies?

Current global estimates indicate that more than 25% of the adult population has diagnosed or undiagnosed hypertension [1], and as a consequence of that, cardiovascular disease and stroke is emerging as a major contributor to the global burden of death and disability [2], [3]. Also alarming is that the prevalence of hypertension is increasing [1], so that by 2025, the expected number of hypertensive patients in the world will be more than 1.5 billion. The majority of hypertensive patients today remain insufficiently controlled [4] and if current strategies of practice do not change, the majority of these 1.5 billion people will remain insufficiently controlled for their hypertension [5]. Clearly, drastic measures have to be taken to improve the current situation and there is an urgent need to prepare health service providers as well as physicians for a global scenario containing even larger patient cohorts, possessing even more complicated and deranged risk‐factor profiles to bring under control.

While the prevalence of hypertension in the community is alarming, even more disturbing is how badly blood pressure (BP) is controlled in patients who are known to be hypertensive. Increased efforts and an extended use of combination therapies are vital to reach BP goals of <140/90 mmHg in patients with uncomplicated hypertension and <130/80 mmHg in those with hypertension and diabetes or renal disease [6]. The severity of hypertension and presence of underlying co‐morbidity should guide the clinician in choosing the optimal type and dosage of antihypertensive therapy. For most patients, treatment does not bring any immediate or subjective benefits to them but rather causes inconvenience, medication‐related side‐effects and substantial costs. All of these factors influence compliance and the risk of suboptimal treatment results. Treatment failure may also be related to suboptimal drug therapy with low doses, inappropriate or wrong dose schedules, or suboptimal use of available treatment combinations.

For a proportion of patients with hypertension, a stepwise approach either starting with one substance or with a fixed low‐dose combination is adequate. A majority of patients with arterial hypertension do not reach BP goals with one antihypertensive drug alone, since patients with higher initial BP demonstrate remarkably lower responder rates to monotherapy [7]. Combination therapy therefore has to be used in a majority of patients with moderate or severe hypertension. In fact, only about 5–25% of such patients can be effectively treated with a monotherapy [8], [10]. Further, in such patient groups, treatment with not two concomitant medications but three or more substances is required [8–10]. As a consequence of this, it may be advantageous for some of these patients to initiate their treatment with a fixed combination within a therapeutic range of components, thereby achieving BP goals more rapidly.

Accordingly, the 2003 ESH/ESC Guidelines [11] recommends that drug therapy should be started gradually either with monotherapy or with a “low‐dose” combination, irrespective of initial BP levels; the JNC 7 report states that most patients with “stage 2” hypertension (systolic BP⩾160 mmHg or diastolic BP⩾100 mmHg) will require a combination therapy. There is no recommendation in the current guidelines on special patient groups to be considered for a first‐line combination therapy, and in the ESH/ESC Guidelines [11], first‐line combination treatment covers both sub‐therapeutic and low therapeutic doses of the mono‐components. In addition and importantly, several trials have found combination therapy to be superior to monotherapy in achieving BP reduction and in minimizing side‐effects [12–14].

In the current issue of Blood Pressure, Jamerson and coworkers [15] provide interesting data from the ACCOMPLISH trial, comparing the efficacy of two types of fixed‐drug combinations as initial antihypertensive therapy. The hypothesis in the ACCOMPLISH trial is that the benazepril/amlodipine combination will be more effective than the benazepril/hydrochlorothiazide combination in reducing major cardiovascular endpoints. What is interesting is that by using the strategy of initiating treatment with a fixed combination, a goal BP of <140/90 mmHg was achieved in 73% of patients within 6 months. Also interesting is that a majority of those not yet controlled had not been offered maximum therapy, indicating that an even greater proportion of patients, when the study advances, will have their BPs controlled by using a fixed‐combination first‐line strategy.

Clearly, so far there are strong indications from the ACCOMPLISH trial that a strategy of initiating antihypertensive therapy with a fixed‐combination is highly effective. Interestingly, both hypertension guidelines [6], [11] and regulatory authorities [16] now reconsider their position on the use of fixed‐drug combinations on high‐risk hypertensive patients.

Obviously, the majority of patients will require more than one drug to control their hypertension. The use of low‐dose fixed‐combination therapy is justifiable as a safe and effective approach to initiating therapy. It allows maximization of each constituent drug's mode of action while minimizing, or even offsetting, side‐effects. BP may be controlled more easily and with fewer clinical visits and a shorter titration period. Patient compliance would be optimized, the risk of switching and poor persistence of therapy avoided, and the financial burden of treating hypertension and its sequelae minimized. An increasing evidence base exists to justify the selection of optimal low doses in newer combinations. Rational combinations at appropriate dose offer safety and efficacy in both the short term and with long‐term treatment of hypertension.

Standard practice when pharmacological treatment is indicated in hypertension management has been to begin treatment as monotherapy with one of the first‐line agents at a low dose. If that was not enough to lower BP to goal, treatment could be shifted to an alternative first‐line agent or additional treatment could be chosen from another antihypertensive group to complement the initial treatment. A free rather than fixed‐dose combination strategy was adopted. Fixed‐dose combination therapies may, however, offer benefits such as convenient dosing regimens, increased adherence and lower risk of adverse effects. In this respect, effective and attractive two‐drug combinations include the following: beta‐blocker/calcium‐channel blocker, angiotensin‐converting enzyme (ACE) inhibitor/diuretic, ACE inhibitor/calcium‐channel blocker, angiotensin receptor blocker (ARB)/diuretic and ACE inhibitor/calcium‐channel blocker.

If a fixed‐combination strategy is added to the existing monotherapy strategy as initial strategy for hypertension management, the physician will have six pharmacological strategies (Table I) to alter or complement treatment if the first step does not adequately control BP:

• The first is to use one of the four major classes of drugs in monotherapy and continue upward drug dose titration of their current monotherapy. Since the dose–response curves for most antihypertensive agents is shallow, increasing the dose usually leads only to a modest increase in the antihypertensive response at the cost of more frequent or severe side‐effects.

• The second strategy is to adopt sequential monotherapy strategy and to change the initial choice of drug until an appropriate response is found. However, in the clinical setting there is no simple reliable way to predict which agent will be the most appropriate for an individual patient. Also, for many patients an ideal monotherapy will never be identified.

• The third option after starting with monotherapy is to add a suitable fixed combination, which acts additionally with, and complementary to, the initial treatment choice. For many patients with existing co‐morbidities requiring a specific initial treatment, this may be an attractive choice.

• The fourth option is to use a fixed‐dose combination therapy, and then as second step continue upward titration. Such an approach is simple for the physician and may offer efficacy and tolerability for the patient.

• The fifth option is to use a sequential fixed‐combination strategy, and if not efficacious, to alter the first combination to another alternative until a satisfactory BP reduction is obtained.

• A sixth choice will be to use a fixed combination as initial therapy, and then if that does not control BP, add a suitable monotherapy on top on that.

Faced with these options, many would argue that a judicious approach to prescribing would be to use low‐dose combination products early in treatment. The benefits of the combination selected and actual doses used over monotherapy must, however, be present in each individual case. The two drugs in combination must be established to lower BP by a greater amount than each alone. Lower doses in combination must be as effective as usual monotherapy doses but with fewer side‐effects. If these conditions can be met, the use of two drugs of different classes in low‐dose combination has many potential advantages.

Table I. First‐ and second‐step treatment alternatives in hypertension management if adopting a first‐line strategy of starting with either monotherapy or a fixed‐combination therapy.

	First step	Second step
1.	Monotherapy (one of the four major classes)	Continued upward drug dose titration
2.	Monotherapy	Sequential monotherapy
3.	Monotherapy	Add complementary fixed combination
4.	Fixed combination	Continued upward titration
5.	Fixed combination	Sequential fixed combination
6.	Fixed combination	Add complementary monotherapy

Hypertension is a heterogeneous condition by aetiology as well as in its response to treatment. A combination of two drugs can therefore be argued to increase the likelihood of a favourable response in a given individual, and there may be several good reasons to consider initializing antihypertensive therapy with a fixed combination:

• First, the antihypertensive effect of each of the components may be enhanced, which in appropriate combinations may offer a synergistic rather than simply additive strategy.

• Second, since two well‐balanced drugs in combination may exert their antihypertensive effects by differing modes of action, there may be a potential for a smoother onset and longer duration of action.

• Third, by using low doses of the individual drugs, the incidence of side‐effects from each component may be minimized.

• Fourth, sometimes the combination of two drugs may offset each other's side‐effect profile to some extent, e.g. the use of an ACE inhibitor, which can prevent hypokalaemia caused by a thiazide diuretic, and appropriate beta‐blocker therapy may offset tachycardia caused by some calcium‐channel blockers.

• Fifth, it may be argued that combining drugs with different mechanisms of action may exert at least additive beneficial effects beyond the benefits of BP reduction on target organs.

• Sixth, the patients compliance with treatment may be improved since combination therapies, particularly in low dose, can usually be taken once daily.

• Seventh, there may be important economical health benefits, since dose titration and dose adjustment will be easier, BP targets will be more easily reached, and patients will require fewer clinical or physician visits to achieve appropriate targets.

• Finally, the overall cost of hypertension management may be reduced, since low‐dose combination products may be less costly than each of the components prescribed separately, and prescribing costs may in some countries be less for a single fixed‐dose medication rather than for two separate antihypertensive drugs.

The current use of low‐dose antihypertensive combination treatments varies considerably throughout the world. In the USA, the acceptance of this therapeutic strategy is generally more widespread than in the rest of the world, and several low‐dose combination products are now licensed for first‐line use in the treatment of hypertension. In France and Italy, there is also a tradition among physicians to use combination products more frequently, while in the Scandinavian countries and the UK, the use of fixed combinations in hypertension management is less frequent.

The regulatory background in Europe has been that first‐line indication for fixed combinations in therapeutic doses has not previously been specifically covered by guidelines. The regulatory standpoint on clinical investigation of medicinal products in the treatment of hypertension (CPMP/EWP/238/95 Rev. 1) has earlier referred to fixed‐combination products as a second‐line indication and to a first‐line indication in sub‐therapeutic doses of the two components. In an updated document from last year (CHMP/EWP/358529/2006) [16], the EMEA argues that fixed‐combination medicinal products may be considered in general if there is an improvement in the benefit/risk assessment, related to the addition or potentiation of therapeutic activities, or related to counteracting adverse reactions. In special instances, they argue that a simplification of the therapy, which improves patient compliance, may also justify the use of a fixed combination. On the other hand, difficulties in individualizing therapy, and the possible addition of different adverse reactions, may create disadvantages that have to be considered when adopting a fixed‐dose combination strategy.

Thus, there are many reasons to believe that the current therapeutic thinking is in a position to change in terms of first‐line treatment of hypertension. Instead of spending time and money on trying to predict individual responses from individual drug regimens, and combining drugs on an empirical basis, we will probably in the near future face a broader use of rational combinations of drugs with different and complementary modes of action. In particular, the use of synergistic combinations with enhanced antihypertensive efficacy, allowing for lower doses of component drugs, will provide possibilities for enhanced antihypertensive effects and fewer dose‐dependent adverse effects. Consequently, this is likely to result in a better patient compliance and improved cost‐effectiveness. Up until now, most outcome trials in hypertension have concentrated on comparing individual antihypertensive agents. The ACCOMPLISH trial places us in a new era of comparing combinations of antihypertensive regimens. One obvious outcome of this will be that the updated guidelines on the management of hypertension will be more likely to emphasize tight BP control, especially for the large proportion of patients at high cardiovascular risk.