When more than two drugs are needed to further decrease blood pressure






Adam GREENSTEIN
PhD, MRCP, FAHA

Tony HEAGERTY
MD, FRCP, FAHA, FMedSci
Kaivan KHAVANDI
MRes, MBChB
Institute of Cardiovascular Sciences, University of Manchester, Manchester
UNITED KINGDOM

When more than two drugs are needed to further decrease blood pressure


by A. Greens tein, K. Khavandi, and T. Heager ty, United Kingdom



The risk conferred by high blood pressure is continuous, and follows a linear association with all adverse cardiovascular events. Epidemiological studies inform us that hypertension is on the rise, driven by an increasingly unhealthy society and a pandemic of obesity. Unfortunately, a substantial number of individuals will be unaware of their condition, and therefore left unprotected against multiple target organ insults. More frustrating still, a very significant proportion of those being treated for high blood pressure fail to achieve adequate control, and thereby remain subject to an unacceptably high risk of cardiovascular morbidity and mortality. National and international guidelines have consistently emphasized the importance of prompt and effective intervention to reduce blood pressure to recommended levels. Following trial data, combination therapies with multiple antihypertensive agents havebeen advocated, and conscious efforts made to alert clinicians to the dangers of untreated hypertension, while simultaneously reducing prescriber anxiety when administering multiple antihypertensives. Sadly, we remain conservative in our approach to blood pressure management, and although a fraction of individuals has genuine resistant hypertension, physician inertia and patient nonadherence is responsible for the majority of cases of suboptimal control. Herein, we discuss these contributing factors in more detail, and summarize society recommendations, the scientific rationale, and trial data to support and guide clinicians in managing patients who require more than two antihypertensive agents to control their blood pressure.

Medicographia. 2013;35:403-410 (see French abstract on page 410)



Hypertension is now the world’s leading cause of death.1 Although the pharmacological tools to treat blood pressure successfully have been available for many years, most patients are not well controlled. Evidence shows that above a certain threshold (140/90 mm Hg), the risk of cardiovascular disease is clear and merits treatment. However, despite vigorously published and publicized guidelines, the majority of published studies show that only half of treated patients achieve satisfactory control. Reasons underlying this phenomenon are multiple and complex, but it is undeniable that a large proportion of patients have difficulty taking their medication due to side effects. This article briefly reviews the reasons underlying poor compliance and outlines some of the innovative new ideas for early treatment with a single pill containing a triple combination of drugs. Evidence is now emerging that this is a safe and effective way to treat hypertension which merits further consideration as guidelines evolve.

Resistant or “resisting” hypertension?

It is an unfortunate reality for clinicians who treat hypertension that one of the major obstacles to achieving satisfactory control of blood pressure in patients is compliance with medication. Hypertension is a very different disease to most other chronic medical conditions. In heart failure, for example, treatment often rapidly improves debilitating symptoms such as breathlessness. By contrast, hypertension is asymptomatic for the majority of patients. Elevated blood pressure is usually detected at a health-screening visit to a primary care or occupational physician and therapy is then started on the basis of guidelines promoting primary prevention of cardiovascular disease. Thus, hypertensive patients move quickly from self-perceived health to a position where they are worried about their health and are taking a daily medicine for the first time in their life. Based on current guidelines, the initial therapy is likely to be either an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker (CCB). The previously asymptomatic patient may then variably experience cough, swollen ankles, skin rashes, flushing, or chest pain while acclimatizing to a new therapy. Within the space of six months or so, this patient is likely to be informed by their clinician that their blood pressure is “not controlled” or is even “out of control.” A new medication will be added, and over the subsequent three to four years there will be changes and modifications to doses and regimens. Successful treatment is judged by prevention of disease rather than amelioration of symptoms. It is no wonder, then, that patients are often less enthusiastic about their treatment than we would like.








Although perhaps overly bleak, this picture of routine hypertension care is strongly supported by study evidence. First, and most importantly, there is overwhelming data to show that higher blood pressure is associated with increased incidence of cardiovascular disease and that treatment can reverse this. Thus, a 20-mm Hg difference in systolic blood pressure is associated with a two-fold increase in cardiovascular risk.2 Conversely, it is only necessary to achieve a 10-mm Hg reduction in systolic blood pressure in 11 hypertensive patients to prevent one cardiovascular death.3 The initiative for the motivated clinician is therefore both clear and compelling. Furthermore, there are now clear guidelines from national bodies which consistently indicate that, in at risk individuals, blood pressure should be reduced to below 140/90 mm Hg.4,5 Despite the availability of both medications and guidance, blood pressure is still very poorly controlled in treated patients. In the USA, data from NHANES (National Health And Nutrition Examination Survey) show that only around 50% of treated patients have blood pressures below 140/90 mm Hg.6 In Europe, the picture is possibly even worse, with up to two-thirds of all patients inadequately controlled.7

There are several reasons why blood pressure tends to be poorly controlled in treated patients. Drugs may be ineffective or the patient may have resistant hypertension. However, poor control is more likely to have resulted from drug side effects, which lead to poor compliance, or—as is increasingly recognized—inadequate control of blood pressure is due to a phenomenon known as “physician inertia.” Physician inertia is recognized but understudied, and is certainly under addressed. It represents the apparent reluctance of a doctor treating a hypertensive patient to escalate or maximize therapy when blood pressure remains above the recommended threshold. The most notable study of physician inertia demonstrated that, in a cohort of over 7000 patients with hypertension, antihypertensive therapy was increased in only 13.1% of clinic visits in patients where blood pressure was above 140/90 mm Hg.8 Furthermore, patients treated by clinicians who did not show therapeutic inertia were 33 times more likely to achieve control of blood pressure than those patients under the care of clinicians with high levels of therapeutic inertia.8 A further important point, which may not always be appreciated by the treating clinician, is that treatment with only one drug is unlikely to achieve effective control of blood pressure. For example, in elderly patients with previously untreated hypertension, monotherapy will control systolic blood pressure to less than 140 mm Hg in only 15% of patients.9 Indeed, available evidence indicates that for the majority of patients either two or three antihypertensive agents will be needed to achieve satisfactory control.10,11


Figure 1
Figure 1. Recommended potential combinations proposed in the
ESH/ESC Guidelines.

Combinations recommended in the general hypertensive population are represented
as thick lines. The frames indicate classes of agents proven to be beneficial
in controlled intervention trials.
Abbreviations: ACE, angiotensin-converting enzyme; ESC, European Society of
Cardiology; ESH, European Society of Hypertension.
After reference 5: Mancia G et al. J Hypertens. 2007;25(6):1105-1187. © 2007,
Lippincott Williams & Wilkins, Inc.


Guideline recommendations

Hypertension guidelines vary in their recommendations for first line antihypertensive agents, and, therefore, combination therapies differ also. The 7th report of the JNC (JNC7 [The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure]) did not provide definitive recommendations for combination therapy, but did suggest that thiazide diuretics were appropriate first-line agents and should form a component of initial combination therapy.4 JNC 7 also recommended that dual antihypertensive therapy was appropriate in some patients from the outset. This has since been supported by trial data from ACCELERATE (Aliskiren and the Calcium ChannEL block- ER Amlodipine combination as an initial treatment strategy for hypertension),12 although a combination of aliskiren and a CCB was used in this study. The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines were published in 2007,5 and reappraised in 2009. There was again no clear preference for a specific class of antihypertensive agent; instead, the recommendation was to select optimal agents based on the individual, taking into consideration factors such as cardiovascular risk profile, target organ damage, and concomitant disease. Again, there was a strong emphasis on the use of multidrug combinations to achieve blood pressure control, and five potential combinations were proposed for priority use, as illustrated in Figure 1.

Guidelines from the British Hypertension Society (BHS) and National Institute for Health and Clinical Excellence (NICE) were released in 2011, and form the most recent evidence based recommendations available.14 The guideline was structured in a similar format to its predecessor, with a stepped approach to achieving blood pressure control, and recommendations for specific agents determined by age and ethnicity of the individual (Figure 2). In those <55 years of age, an ACE inhibitor is the preferred choice, or a low-cost angiotensin II receptor 1 blocker (ARB) if intolerant of ACE inhibitors (eg, due to cough). Those ≥55 years of age or black people of African or Caribbean decent of any age should commence treatment with a CCB, or if not suitable, a thiazide-like diuretic such as chlorthalidone or indapamide. This is based on the fact that younger patients (excluding black people) have higher renin levels, and therefore receive greater benefit from angiotensin blocking agents, whereas older people and people of African and Caribbean origin tend to have lower renin levels and respond better to CCBs and diuretics. If blood pressure remains elevated, step 2 involves addition of a second agent to give the combination of an ACE inhibitor (or ARB if intolerant) and a CCB (or thiazide-like diuretic if intolerant, or in heart failure). If a third agent is required, a thiazide-like diuretic should be added. If clinic blood pressure remains >140/90 mm Hg after treatment with optimal or best-tolerated doses of a CCB, angiotensin blocker, and thiazide-like diuretic, the disorder is classified as resistant hypertension, and a fourth antihypertensive agent should be considered and expert opinion sought. If potassium is not elevated, further diuretic therapy with low-dose spironolactone can be considered, or if contraindicated/ineffective, an α- or β-blocker.


Figure 2
Figure 2. Algorithm from the NICE/BHS guidelines in 2011, recommending
calcium channel blocker + angiotensin blocking agent
as the only preferred combination, with sequential addition of a
thiazide-like diuretic, further diuretic (spironolactone), and/or α- or
β-blockade.

Abbreviations: BHS, British Hypertension Society; NICE, National Institute for
Health and Clinical Excellence. A = angiotensin-converting enzyme inhibitor or
angiotensin II receptor blocker; C = calcium channel blocker; D = thiazide-like
diuretic.
After reference 14: NICE Clinical Guideline 127. © 2011, National Institute for
Health and Clinical Excellence.


Scientific rationale

Combination therapies should be based on complementary physiological mechanisms of action. The pathophysiology of blood pressure is multifactorial, but the predominant factors are an increased peripheral vascular resistance and elevated cardiac output. A combination regimen should, therefore, aim to target these pathways, for example with an angiotensin blocker to reduce peripheral vascular resistance, a diuretic to reduce excess fluid volume, and β-blockers to reduce the heart rate. However, as peripheral vascular resistance is the primary driver of increased blood pressure, additional benefit may be conferred by vasodilating dihydropyridine CCBs over β-blockers. Mechanistically, therefore, a rational choice might be a renin-angiotensin system (RAS) blocker and aCCB. Third and fourth-line add-on agents should overcome any potential compensatory changes caused by previous medications, which can trigger reflex elevations in blood pressure. For example, the RAS can be activated as a counter-regulatory response to diuretics or CCBs, as a maladaptive response to restore the elevated blood pressure. An angiotensin blocking agent, with a CCB and a thiazide diuretic may, therefore, provide synergistic benefits. Further, when blood pressure control is not achieved with two antihypertensive agents, subjects are likely to have fluid retention,15,16 and treatment with diuretics is often necessary for that reason. Aldosterone excess may also contribute to the development of resistant hypertension, and spironolactone blocks the action of aldosterone at the mineralocorticoid receptor, stimulating natriuresis and alleviating fluid overload. This can also address aldosterone rebound, which is seen with long-term angiotensin blockade, where aldosterone escapes blockade and levels return to baseline.17 Deriving rational pharmacological combinations from such principles has, unsurprisingly, lead to discrepancies in practice—for example with some promoting the combination of dihydropyridine and nondihydropyridine CCBs, while others support the use of high-dose nitrates and direct vasodilators or α-agonists. It is therefore necessary to evaluate trial evidence to confirm which combinations carry the best evidence.

Current evidence

High blood pressure investigation is one of the most evidence rich areas in medical research, and patients have benefited significantly from application of evidence-based recommendations. However, when taken collectively, the literature concerning combination therapies (with more than two drugs) is not structured, with comparator trials including a mix of monotherapy and placebo, with a variety of different add-on agents, and no definitive head-to-head comparisons for combination regimens with two or more drugs. Data has, therefore, been extrapolated from the efficacy of agents as monotherapy, or as dual combinations.

Diuretics were prominent in early guideline recommendations. This was based on evidence of their efficacy as monotherapy in trials such as SHEP18 (Systolic Hypertension in the Elderly Program) and Syst-Eur19 (Systolic Hypertension in Europe), but primarily driven by their low cost. More recent comparator trials such as ACCOMPLISH20 (Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension), ASCOT-BPLA21 (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm), and ANBP222 (second Australian National Blood Pressure Study), have shown thiazide diuretics as inferior to their comparators in preventing adverse cardiovascular end points. Consequently, there has been a decline in the use of diuretic prescriptions for the treatment of hypertension in recent years. If used, thiazide- like diuretics are preferred over true thiazides. Data from ADVANCE23 (Action in Diabetes and Vascular disease: Preter- Ax and DiamicroN MR Controlled Evaluation) and HYVET24 (Hypertension in the Very Elderly Trial) support the use of perindopril/ indapamide combinations in high-risk diabetic patients and hypertensive individuals over 80 years of age, respectively.

The LIFE trial (Losartan Intervention For Endpoint reduction in hypertension)21 supported the use of an ARB over a βblocker in combination with a thiazide diuretic, with a reduced composite cardiovascular end point (driven by improvement in rates of stroke). Now that ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) has unequivocally showed that perindopril plus amlodipine was superior to atenolol and thiazide diuretic in normalizing blood pressure parameters and preventing cardiovascular events,21 β-blockers have fallen out of favor, which is reflected by their exclusion as preferred agents in the recent NICE guidance.The ASCOT and ACCOMPLISH20 trials (Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension) support the use of an angiotensin-blocking agent in combination with a CCB as superior in preventing cardiovascular end points. There is some debate about class benefits independent of blood pressure lowering, with some evidence that CCBs are preferential in stroke, and ACE inhibitors in coronary heart disease,25 above and beyond blood pressure lowering. However, the general focus over recent years has been to prioritize blood pressure lowering, which ultimately remains the absolute priority.26 A number of important secondary analyses of ASCOT have, however, provided evidence of additional benefits for this combination, above and beyond greater blood pressure control,27 including reduced incidence of diabetes,28 reduced blood pressure variability,29 superior reduction in central blood pressure,30 and indirect measures of improved arterial remodeling and peripheral vascular resistance.31 Additional RAS blockade achieved by combining an ACE inhibitor with an ARB did not confer any additional cardiovascular benefit in ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), and produced increased adverse renal outcomes,32 despite a slight reduction in blood pressure.33 There is limited evidence for direct renin inhibition, although a recent trial of type 2 diabetic patients failed to show any benefit from the addition of aliskiren to either an ARB or ACE inhibitor, for cardiac or renal end points.32

There is no robust evidence to guide the selection of a third antihypertensive agent.34,35 Chlorthalidone (ALLHAT [Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial] and SHEP) and spironolactone have particular efficacy in lowering blood pressure in resistant hypertension,36,37 although indapamide has a more favorable metabolic profile and has demonstrated strong mortality reduction. In ASCOTBPLA, spironolactone38 was used as a fourth-line add-on agent in resistant hypertension, which was well tolerated at low doses and produced significant additive blood pressure– lowering benefits. If side effects such as gynecomastia and breast tenderness are experienced, consideration can be made for the more selective mineralocorticoid receptor blocker eplerenone. Amiloride is another suitable substitute, although it would require increased doses.34 Side effects with spironolactone are related to duration/dose, and are normally reversible upon discontinuation of treatment. Electrolytes and renal function must be monitored within two weeks of initiating these agents, and with subsequent follow-up depending on baseline values and dosage. If potassium is elevated, the dose of the thiazide-like diuretic can be increased. In ASCOT-BPLA, doxazosin gastrointestinal therapeutic system was used as the third-line agent for both of the blood pressure–lowering treatment regimens,39 and afforded sustained blood pressure– lowering effects without adverse effects on heart failure (in contrast to ALLHAT) or lipids. The recent concept of sequential nephron blockade was proposed as a strategy in resistant hypertension.40 It is centered on countering intrarenal compensatory sodium reabsorption at unblocked nephron sites through stepped addition of low doses of four different diuretics, working at different sites. In those individuals unable to achieve blood pressure control on triple therapy with an ARB, thiazide, and CCB, sequential nephron blockade achieved blood pressure control in 58% of patients, compared with 20% in patients treated with sequential RAS blockade.

Nonadherence

When taken together, what is clear from the above data is that a number of antihypertensive agents are available and have proven efficacy in decreasing blood pressure and reducing cardiovascular risk. Even accounting for physician inertia, it seems surprising that quite so many “treated” individuals have uncontrolled hypertension. Of course, the bulk of responsibility for control of blood pressure lies with the patient. If they are compliant with their medication, then it is far more likely that they will achieve a satisfactory blood pressure. However, published studies indicate that compliance with prescribed antihypertensive medication may be as low as 25% to 50%.41 Reasons for noncompliance are complex, but can be divided into intentional and unintentional reasons. Intentional nonadherence is usually due to the side effects of medications and compounded by lack of communication between the doctor and patient regarding the importance of good blood pressure control. Unintentional nonadherence is more common in elderly patients, who are more likely to be on complex medication regimens or may forget to take their tablets.

It is for all of these reasons that single-pill combination treatments (also known as fixed drug combinations) are increasingly used in patients with hypertension. Thiazide diuretics are the most common components, usually combined with ACE Inhibitors, ARBs, or β-blockers. Combinations including dihydropyridine CCBs are also available and increasingly popular. These single-pill combination regimens are used much more sparingly for hypertension management in the UK (2% of all antihypertensive prescriptions) compared with the rest of Europe (40%-50% of prescriptions),42 despite evidence that their use is associated with improved adherence and blood pressure control.5,43,44 Reluctance to prescribe fixed drug combinations is often due to concerns regarding cost. However, a retrospective analysis of a UK primary care database of over 25 000 patients treated for hypertension has shown that patients on single-pill combination treatments attain significantly better blood pressure control than those on individual drug regimens.42 Subsequently, although prescription costs were higher in the group taking the single-pill combination treatments, cardiovascular event rates (and thus, overall management cost per patient) were higher for those on individual drug regimens.

The use of single-pill combination treatments for initial therapy in hypertension therefore confers a number of important advantages over starting treatment with a single drug. First, it is a reality that most patients will need at least two drugs to control their blood pressure. Thus, initiation with a combination treatment is more likely to achieve a rapid and effective reduction in blood pressure compared with monotherapy. Second, judicious combination of therapies may actually reduce side effects. For example, the side effect that most commonly limits the use of CCBs is ankle edema. However, when CCBs are used in combination with an ACE inhibitor or an ARB, the incidence of ankle edema is significantly reduced.45,46,47 Therefore, when used appropriately, the single-pill combination approach has the potential to fundamentally alter the initial management of hypertension. It is interesting to reflect on the Veterans Affairs Cooperative Study from the 1960s, which was the first clinical trial to show prevention of adverse cardiovascular events with effective pharmacological treatment of hypertension. The study adopted a triple-drug combination consisting of reserpine, hydralazine, and hydrochlorothiazide,48 which was highly effective but associated with significant side effects. This prompted the paradigm change to the now familiar stepped therapy approach, where practitioners start with a single therapy and then titrate this up to the maximum tolerated dose. However, using the single-pill combination approach, multiple drugs can be initiated at lower doses than those which might be expected to have an effect individually, and there is evidence that this is associated with more effective blood pressure control.49 Furthermore, because lower doses of the individual components of the combination pill can be used, side effects are less likely to occur than when titrating a single agent up to a maximum.

More recently, commercially available single-pill combination treatments have included three drugs: an ARB, a CCB, and a thiazide diuretic. The use of these three drug classes reflects the evidence from a number of clinical studies. STITCH (Simplified Therapeutic Intervention To Control Hypertension) compared a treat-to-goal protocol starting with an ARB or ACE inhibitor combined with a thiazide diuretic, with subsequent addition of a CCB against conventional care based on national guidelines. The study demonstrated that the triple combination therapy was well tolerated and achieved a greater degree of blood pressure control compared with a guideline based approach within the study period of six months (intervention group, 64.7% vs control group, 52.4%; P=0.026).50

In the TRINITY study by Oparil and colleagues (TRIple therapy with olmesartaN medoxomIl, amlodipine besylaTe, and hYdrochlorothiazide in adult patients with hypertension), initial triple therapy with olmesartan, amlodipine, and hydrochlorothiazide was compared with dual combination or placebo in hypertensive patients. After three months, 69% of patients on triple combination therapy had achieved target blood pressures of ≤140/90 mm Hg compared with only 41%-53% of patients on dual combination therapy.51 Of the 2400 patients treated, only 52 patients discontinued therapy due to adverse effects (4% drop-out rate in the triple combination group vs 1%-2% in the dual combination group). In a study in a cohort with diastolic hypertension, the fixed-dose combination of valsartan, amlodipine, and hydrochlorothiazide was shown to reduce blood pressure to a greater extent than any of the dual therapy combinations of the same drugs, with a significantly higher rate of blood pressure control (71% vs 45%-54%).52 A number of new fixed-dose combinations including triple therapies have been approved for the treatment of hypertension. Aliskiren has been approved in combination with hydrochlorothiazide, amlodipine, or as a fixed-dose combination of the three.

Conclusions

Reducing blood pressure has become an international priority. Hypertension is now the biggest killer in the world, and its incidence is growing as a result of overweight and obesity. Among those individuals with known hypertension who are receiving treatment, a significant number have uncontrolled hypertension and are left unprotected from adverse cardiovascular events. Ultimately, many of these individuals will succumb to premature cardiovascular death as a direct consequence of this. National and international guidelines encourage aggressive blood pressure control and, in keeping with trial data, support combination regimens to achieve this. Current evidence supports the use of a CCB and an angiotensin- blocking agent for dual therapy. The evidence is less robust for the choice of further agents, but a thiazide-like diuretic, followed by spironolactone and then doxazosin represent rational add-on agents with some supporting evidence. The BHS Collaborative Research Working Party has initiated the PATHWAY studies (Prevention And Treatment of resistant Hypertension with Algorithm guided therapy) to investigate the best approach to the treatment of resistant hypertension.34 Although it is interesting (and important) to dissect the data and determine precise combination regimens with the most evidence, in reality it is unlikely that there will be an optimal three- to four-drug combination to suit everyone. Conversely, it is probable that if patients were prescribed, and adhered to, current recommended combination therapies based on complimentary pharmacology, the majority would achieve satisfactory blood pressure control. At the prescribers’ end, the promotion of the recent national guidelines issued by NICE/BHS will encourage practitioners to comply with evidence-based recommendations and the frequent need to adopt multi-combination therapies. As hypertension is a stealth condition, public health campaigns to raise awareness of the risks of high blood pressure will increase adherence. Fixed-dose combinations will likely improve things at both ends of the stethoscope. These interventions should be combined with diet and lifestyle campaigns, which will ultimately prevent hypertension in most cases. We cannot afford to take a casual approach to high blood pressure treatment, and the “conservative” approach, which is so often adopted, equates to delayed or failed control, and a number of avoidable cardiovascular deaths.


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Keywords: blood pressure control, combination; compliance; guidelines; hypertension; therapeutic inertia