Need for fixed-dose combination therapy in the early phases of hypertension

Internal Medicine and Physiology,
University of Michigan Cardiovascular Medicine,
Ann Arbor, Michigan

by S. Julius,USA

Stage 1 hypertension is the most prevalent form of hypertension and because of its frequency it has a large impact on public health. Nearly two thirds of all hypertension-related coronary deaths occur in stage 1 hypertension. Current treatment of stage 1 hypertension is based on old studies, when the side effects of drugs dictated a slow, stepwise increase in medication dosage. This might not be necessary with new, effective, and fast-acting fixed-combination pills. Hypertension is a self-accelerating condition. Early brisk blood pressure lowering with fixed-combination pills may prevent the development of high-risk hypertension later. Many patients perceive the current approach of repeated clinic visits for dose adjustments in stage 1 hypertension as a failure to achieve blood pressure goals. This discourages adherence to treatment. Physicians’ fear of hypotension with the use of effective drugs in stage 1 hypertension is unwarranted. Blood pressure decrease is proportional to baseline blood pressure level, and the response in stage 1 hypertension is less than that in advanced hypertension. Currently, fixed-combination pills are not approved for treatment of stage 1 hypertension. However, the worldwide failure to control hypertension calls for new approaches. Fixedcombination pills promise safe and fast BP control, better adherence to treatment, and a larger reduction in cardiovascular events in stage 1 hypertension. Changes in clinical practice cannot be implemented without evidence, so there is a need for a trial to verify that the conceptual advantages of fixedcombination pills translate into better outcomes in stage 1 hypertension.

Medicographia. 2010;32:262-268 (see French abstract on page 268)

In this review I will argue that in order to further decrease adverse cardiovascular outcomes, we ought to focus on the treatment of stage 1 hypertension. There are three major reasons why this stage of hypertension deserves renewed attention:

1. Public health impact of stage 1 hypertension

The huge impact of stage 1 hypertension on public health is illustrated in Figure 1, adapted from the impressive Multiple Risk Factor Intervention Trial (MRFIT) follow-up of 122 086 subjects with hypertension on initial screening.1 Over a 15-year observation period, 6293 people in the hypertension group died from coronary heart disease. In MRFIT, hypertension was classified according to the USA Joint National Committee (JNC) 6 guidelines.2 This classification has been superseded by the JNC 7 grading of hypertension,3 but the diastolic blood pressure (DBP) range for stage 1 classification is the same in JNC 6 and JNC 7. In the left panel of Figure 1, the death rate from coronary heart disease is lowest in stage 1 hypertension. The rate increases in a stepwise fashion with each subsequent grade. By stage 4, coronary deaths are three times more likely to occur than in stage 1. However, as the middle panel shows, stage 1 hypertension is the most prevalent form of hypertension (74%), while stage 4 is extremely rare (1.2%). The net result of this is shown in the right panel. The sheer size of the stage 1 group is so overwhelming that despite a relatively low individual risk, most coronary deaths are found in stage 1 hypertension. Conversely, the group with the highest risk is so small that it barely impacts total hypertension- related coronary deaths (3%).

Figure 1
Figure 1. The impact of stage 1 hypertension on coronary heart disease mortality.

Abbreviation: CHD, coronary heart disease.
Adapted after reference 1: Neaton et al. In: Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press Ltd; 1995;1: 127-144. © 1995, Raven Press Ltd.

In clinical practice highly endangered patients command immediate attention, and this fact is partially reflected in hypertension guidelines. Thus JNC 7 guidelines recognize that most patients require two drugs to reach their blood pressure (BP) goals, but suggest initiating treatment of stage 1 hypertension with one drug. More effective treatment with combination pills containing 2 drugs is reserved for stage 2 hypertension. This inadvertently creates the impression that BP control in stage 1 is less important. In fact the reverse is true; to decrease adverse cardiovascular events, we ought to focus on BP control in stage 1 hypertension.

2. Lack of new information about therapy in stage 1 hypertension

Present approaches to stage 1 hypertension are based on outcomes from old studies. The last paper about stage 1 hypertension was published 17 years ago. Since then nothing new has been published about the treatment of stage 1 hypertension.

The first report about mortality in stage 1 hypertension was published 70 years ago.4 Longitudinal observations of millions of people with life insurance policies in the USA clearly demonstrated that longevity negatively correlates with BP levels (Figure 2, page 264). Since effective antihypertensive agents had not yet been invented in 1939, this observation provides a unique view of the natural history of untreated hypertension. What would today be classified as stage 1 hypertension (DBP, 93 to 97 mm Hg) was associated with a 100% increase in total mortality.

Thirty years after the life insurance companies’ report, the US Veterans Administration (VA) published the first in a series of seminal treatment trials in hypertension. They first showed that BP can effectively be reduced with pharmacological treatment5 and next6 reported that pharmacological BP lowering reduced “terminating morbid events” in patients with DBPs of 115 to 129 mm Hg. The effect of treatment was so dramatic that after one year patients receiving placebo were switched to active treatment. The picture was not so clear for DBP in the 90 to 114 mm Hg range, and in this group the trial was continued.

Figure 2
Figure 2. Relationship between diastolic blood pressure levels
and mortality.

Abbreviation: BP, blood pressure.
Adapted after reference 4: Society of Actuaries. Blood Pressure Study 1939.
New York, NY: Society of Actuaries and Association of Life Insurance Medical
Directors; 1940. © 1940, Society of Actuaries and Association of Life Insurance
Medical Directors.

Three years later the VA study reported that patients receiving placebo with DBPs of 90 to 114 mm Hg had a significantly higher incidence of cerebrovascular accidents, congestive heart failure, and accelerated hypertension.7 The incidence of coronary artery events was similar in both arms of the study. The relative risk reduction in morbidity events was 75% in patients with prerandomization DBPs of 105 to 114 mm Hg, but only 35% in the group with DBPs of 90 to 104 mm Hg, a difference that was not statistically significant.

Active drug treatment in the VA study was associated with substantial side effects. Two patients were lost due to the toxicity of apresoline, while serious central nervous side effects of reserpine and α-methyldopa led to the discontinuation of treatment in 29 additional patients.

The unclear results of VA trial participants with DBPs of 90 to 104 mm Hg shaped subsequent outcome studies, and three major new trials were launched to resolve the issue.8-10 Because of the VA experience with treatment-related side effects, the treatment schemes in these trials included careful and slow uptitration of drug dosages.

The upper DBP limit for enrollment in studies of “mild” hypertension (Table I) published from 1979 till 1985 was 5 to 9 mm Hg higher than the current DBP limit for stage 1 hypertension. These older studies used stepwise uptitrations and/or the addition of drugs—starting with diuretics, adding α-methyldopa or apresoline, and eventually adding other drugs—to reach BP goals.

Table I
Table I. Comparison of studies of “mild” hypertension published from 1979 to 1993.

Abbreviations: BP, blood pressure; HDFP, Hypertension Detection and Follow-up Program; HT, hypertension; MRC, Medical Research Council [study]; TOMH, Treatment Of Mild Hypertension [study].

The most recent trial in Table I was substantially different from the other trials.11 Importantly, the enrollment criterion (DBP, 90 to 99 mm Hg) in the Treatment Of Mild Hypertension (TOMH) study was consistent with the current definition of stage 1 hypertension. Furthermore, TOMH patients were randomized either to placebo or to one of four monotherapies with different active antihypertensive agents. The TOMH study introduced an important innovation to the definition of events by also adding other clinical events (hospitalization for transient ischemic attacks, development of angina or intermittent claudication, and signs of peripheral arterial disease) to the usual “hard” end points. Since the population in TOMH was too small to compare the effect of different drugs, the four active treatment groups were pooled and compared to the placebo group.

In all the trials reviewed in Table I, rates of events in the active treatment groups were lower than in the placebo group. In the Hypertension Detection and Follow-up Program (HDFP), total mortality was significantly reduced in the stepped-care group. In the Australian study, significantly lower rates of cardiovascular events were seen in the treatment group. In the Medical Research Council (MRC) trial, strokes and cardiovascular events were reduced in the active treatment groups. In TOMH, the rate was significantly lower in the active treatment group only after “hard” and “other” events were merged into a composite index of events.

Significance levels in these studies were not overwhelming (P<0.01 to P<0.05). It was hoped that TOMH would open the door to studies exploring whether the use of modern, more effective, and better-tolerated antihypertensive agents in stage 1 hypertension would yield superior and more convincing results. The small TOMH study was designed to test the feasibility of a larger trial in “mild” hypertension, but eventually it became the model for ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial)12 in high-risk hypertension.

3. The exponential nature of untreated hypertension

We have shown in the Tecumseh study (Figure 3) that hypertension starts very early and that with the passage of time BP begins to increase in a steep, nonlinear fashion.13 Subjects that in 1990 were classified as having “borderline” hypertension would currently be classified as having stage 1 diastolic hypertension (average DBP, 93 mm Hg). This group already had a significantly higher BP level at 6 years of age. In the second decade of life their BP remained higher than that of the normotensive group, but did not reach the hypertensive range.

However, in subjects destined to become hypertensive, BP increased steeply from normal values in the second decade of life to hypertensive values at 31 years of age. We call this abrupt increase in BP, “self-acceleration,” as it largely reflects the consequences of previous milder BP elevation. Prolonged mild BP elevation suffices to elicit a restructuring of resistance vessels (arterioles) and to cause endothelial damage in these vessels. Restructured arterioles in stage 1 hypertension respond excessively to all constrictive stimuli.14 These structural changes also reduce the arteriolar lumen and render arterioles less responsive to vasodilation. The ensuing endothelial dysfunction further reduces vasodilation capacity in the early phases of hypertension. Thus patients with stage 1 hypertension are already on the path to further hypertension acceleration, and early BP lowering is the only way to interrupt the process. If the BP in these subjects is not lowered in a timely fashion, target-organ consequences of hypertension are bound to develop.

Since the processes described above reflect previous BP elevation, it stands to reason that the earlier treatment is started and the faster BP is controlled, the better the patient’s prognosis. New better tolerated, more effective drugs promise better BP control, quicker BP lowering, and improved patient adherence to treatment. Unfortunately, the subsequent research focus jumped from stage 1 to high-risk hypertension, and we have no information about new therapeutic approaches to stage 1 hypertension.

Figure 3
Figure 3. Longitudinal blood pressure trends in the Tecumseh

Subjects were classified as having borderline hypertension or normal blood pressure when they were 31 years old. Their previous blood pressures values were retrieved from records of preceding Tecumseh health exams.
Modified after reference 13: Julius et al. JAMA. 1990;264:354-358. © 1990, American Medical Association.

In the absence of new data, the US JNC 7 guidelines extrapolated findings from studies of advanced high-risk hypertension and applied them to the treatment of stage 1 hypertension.3 This is plainly wrong. There is a world of difference between stage 1 and high-risk hypertension. The treatment goal in stage 1 hypertension is to prevent vascular damage caused by high BP. In high-risk patients the goal is to postpone the clinical consequences of preexisting vascular damage. Hypertension is a disease of multiple competing cardiovascular risk factors. In the early phases of hypertension a higher BP is already associated with pressure-independent cardiovascular risk factors, such as obesity, high hematocrit, tachycardia, higher glucose and insulin levels, and dyslipidemia.13 Over the course of hypertension, the progression of most of these abnormalities accelerates, and target organ damage starts to develop in parallel. If target organ changes such as arteriolar and left ventricular hypertrophy, coronary atherosclerosis, nephrosclerosis, and decreased distensibility of large conduit arteries have already developed, the patient may have reached the point of no return. Beyond this point, BP lowering will ameliorate and postpone cardiovascular events, but will not fully reverse the underlying processes. Moreover, life expectancy in these aged patients is substantially shorter than in stage 1 hypertension.

Here is one example to illustrate what happens when physiological thinking is ignored and data from high-risk hypertension are extrapolated to stage 1 hypertension. In the ALLHAT12 study of high-risk hypertension the incidence of new-onset diabetes was significantly higher in the group treated with diuretics than in other treatment groups. However, over the 5- year observation period the incidence of adverse cardiovascular events in the new-onset diabetes group did not increase. Cardiovascular consequences of type 2 diabetes greatly increase patients’ risks ofmorbidity andmortality, but they evolve in a slow, insidious fashion over a patient’s entire adult life span.

Admittedly, during the short observation period in ALLHAT, new-onset diabetes was not associated with more adverse cardiovascular events, but does that mean that inducing abnormalities of glucose metabolism in stage 1 hypertension will prove to be innocuous? Typically stage 1 hypertension is diagnosed in the third decade of life and the patient will subsequently require 30 to 40 years of treatment. Nevertheless observations in ALLHAT provided the basis for the JNC 7 recommendation3 that diabetes-inducing diuretics similar to the one used in ALLHAT ought to be the first step in the treatment of stage 1 hypertension. Apparently in the era of evidencebased medicine, absence of evidence can be viewed as evidence. Does this really make sense?

A positive example of clinical need changing a treatment paradigm in younger patients with arterial hypertension comes from the latest UK guidelines reported by the National Institute for Clinical Excellence and the British Hypertension Society.15 These guidelines called for the selection of first-line drugs based on the age of hypertensive patients, advocating treatment with a drug that blocks the renin system (angiotensinconverting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB], in the case of ACE inhibitor intolerance) in younger subjects (<55 years), whereas in older subjects and blacks, in whom a low renin status is more common, a calcium channel blocker (CCB) or thiazide diuretic is recommended. The reason for these changes come fromthe Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm (ASCOT-BPLA), which although not specifically designed in stage 1 hypertension nevertheless recruited 19 257 hypertensive patients at mild risk of experiencing a cardiovascular event without clinical evidence of coronary artery disease or heart failure. The ASCOT-BPLA trial was terminated prematurely due to significantly lesser rates of all-cause mortality (11%), cardiovascular mortality (24%), stroke events (30%), and new-onset diabetes (32%) in patients allocated an amlodipine± perindopril regimen compared to those allocated an atenolol±bendroflumethiazide regimen (Table II).16

Table II
Table II. Main results of the ASCOT-BPLA study.

Treatment with amlodipine/perindopril yielded better outcomes than traditional treatment with atenolol/thiazide, despite good BP control in both treatment arms.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CHD, coronary heart disease; CV, cardiovascular; MI, myocardial infarction; RRR, relative risk reduction.
Modified after reference 16: Poulter et al; ASCOT Investigators. Lancet. 2005; 366:907-913. © 2005, Elsevier Ltd.

Fixed-dose–combination pills in stage 1 hypertension

Fixed-combination pills, which are currently denied to stage 1 patients, are well tolerated, decrease BP in a very efficient fashion, and provide quicker BP control. Two categories of currently available fixed-dose medications are of particular interest. First are pills that contain a diuretic and a drug that interferes with the renin-angiotensin system (RAS), like ACE inhibitors, ARBs, or renin inhibitors. The second group are pills that combine a CCB with a drug that interferes with the RAS. Both these categories decrease BP efficiently and are well tolerated. Other combinations, particularly those containing β-blockers, are less useful.

It is unlikely that all pills combining diuretics with RAS blockers are equal. In selecting such a pill the physician must evaluate the dose and the type of diuretic used. Some potent diuretics in larger doses invariably interfere with glucose metabolism. Particularly notorious is chlorthalidone. In the large Systolic Hypertension in the Elderly Programme (SHEP)17 and in ALLHAT, chlorthalidone was associated with an increase in new-onset diabetes. Combinations that contain a small amount of diuretic and offer a wide range of RAS inhibition are preferable. Some diuretics are “glucose friendly”18 and are very efficacious when combined with drugs that interfere with the RAS.19 There are also substantial differences between the var- ious RAS and CCB combinations. Tablets containing a longacting dihydropyridine CCB are likely to be more efficacious— especially when combined with a long-acting RAS inhibitor (for example, the amlodipine/perindopril regimen of ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial])—than ones containing verapamil or diltiazem. In an attempt to imitate habitual stepwise uptitration, some products are composed of numerous tablets, each with a different dose of basic ingredient. This defeats the purpose of a combination pill. Combination products should efficiently decrease BP and require no more than a single uptitration step.

Experts in the field agree that quick BP lowering is also a physiological imperative in stage 1 hypertension. BP-related target-organ damage is seen in prehypertension and is widespread in stage 1 hypertension. Decreased maximal forearm vasodilation, an early sign of vascular restructuring, has been documented in patients with borderline hypertension13 and, to a larger degree, also in stage 1 hypertension.14 Inadequate vasodilation was also documented in a physical exercise study of subjects with borderline hypertension.20 During exercise, cardiac output increased and vascular resistance decreased with increasing workload. In other words, exercise induces generalized vasodilation to accommodate the increased blood flow. At the point of maximum achievable exercise, subjects with borderline hypertension had much higher vascular resistance than healthy volunteers. Thus, the strong stimulus of exercise failed to elicit appropriate vasodilation in subjects with borderline hypertension.

Many subjects with borderline hypertension and stage 1 hypertension show signs of cardiac restructuring. A decrease in stroke volume has been described in prehypertension21 and stage 1 hypertension.22 Prehypertension and stage 1 hypertension are associated with tachycardia, which may limit stroke volume. However, an even more substantial stroke volume decrease was seen after blockade of cardiac autonomic nervous receptors.21 Cardiopulmonary blood volume, a measure of cardiac venous filling, was normal in these patients. Thus low stroke volume after chemical denervation of the heart is due to increased cardiac stiffness. Higher cardiac stiffness in early phases of hypertension is associated with echocardiographic signs13 of impaired ventricular diastolic relaxation (E/A ratio). Importantly, longitudinal observation22 has demonstrated a further and more prominent decrease of stroke volume over the course of hypertension. Long-standing BP differences between the placebo and actively treated groups in the TOMH study of stage 1 hypertension11 were associated with electrocardiographic changes indicative of increased left ventricular mass in the placebo group.

With this background in mind, one must conclude that nothing will be gained by postponing effective antihypertensive treatment in stage 1 hypertension. Similarly, slow stepwise uptitration of medication offers no advantage. The stepwise approach was justified when drugs were poorly tolerated and physicians had to search for the lowest possible effective dose. Besides the conceptual rationale suggesting that early, brisk BP lowering is advantageous, there is also a practical reason to embrace a more aggressive stance in the treatment of stage 1 hypertension. Patients’ poor adherence to prescribed medication is a notorious problem in the treatment of hypertension. The problem is even greater in patients who perceive that their BP is just a “little bit elevated” because they feel healthy and are not convinced that treatment is necessary. The earlier physicians can tell patients that their BPs have been brought under control, the more likely they are to comply with taking their medication. We live in a success-oriented environment where failure is not welcome. Many a patient disappointed by his doctor’s slow search for the right dose will either find another practitioner or will simply give up.

Nevertheless, fear of hypotension may deter physicians from using fixed-dose–combination pills for the treatment of stage 1 hypertension. This is a legitimate concern that needs to be resolved with a clinical trial. However, I will dare to predict that patients with stage 1 hypertension tolerate combination pills very well. It is not generally appreciated that the higher the baseline BP, the bigger the BP decrease for a given dose of antihypertensive medication. By the same token, the lower the baseline BP, the lower the BP lowering. Contrary to the general perception that lowering BP in “mild” hypertension is easy, it is actually quite difficult to reach the target BP decrease in stage 1 hypertension. It seems that the closer one gets to a BP reading of 120/80 mm Hg, the more the body opposes further BP lowering. I am particularly encouraged by the results of TROPHY (TRial Of Preventing HYpertension) in prehypertension,23 where treatment elicited BP lowering of 10/5 mm Hg and none of the patients reported major signs of hypotension. In summary, prompter BP lowering in highly prevalent stage 1 hypertension may have a major positive impact on public health and is likely to be well tolerated. _

1. Neaton JD, Kuller L, Stamler J, Wentworth DN. Impact of systolic and diastolic blood pressure on cardiovascular mortality. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press Ltd; 1995;1:127-144.
2. National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446.
3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
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5. Veterans Administration Cooperative Study on Anti Hypertensive Agents. A double-blind control study of antihypertensive agents: I: Comparative effects of reserpine and hydralazine, and three ganglionic blocking agents. Arch Intern Med. 1960;106:81-96.
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17. Shafi T, Appel LJ, Miller ER 3rd, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008;52:1022-1029.
18. Marre M, Garcia-Puig J, Kobot F, et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR study (Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with micrOalbuminuRia). J Hypertens. 2004;22:1613- 1622.
19. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial); a randomized controlled trial. Lancet. 2007;370:829-840.
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21. Julius S, Randall OS, Esler MD, Kashima T, Ellis CN, Bennett J. Altered cardiac responsiveness and regulation in the normal cardiac output type of borderline hypertension. Circ Res. 1975;36-37(suppl. I):199-207.
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Keywords: fixed-dose combination; fixed-combination pill; stage 1 hypertension