Developments in the Treatment of Hypertension

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Hypertension (HT) remains the most common preventable risk factor for cardiovascular (CV) morbidity and mortality. There are exciting new data about epidemiology, brachial blood pressure (BP), ambulatory blood pressure monitoring (ABPM) and pre-hypertension from large clinical trials.

Increasing Burden of Hypertension Worldwide

The incidence of HT is rising worldwide due to common environmental factors. These include excessive dietary sodium, obesity, physical inactivity, alcohol intake, psychological stress and increased survival of ageing populations. In 2000, 972 million people were thought to be hypertensive, and this is projected to increase by 60% to a total of 1.56 billion (or 29% of the worldwide adult population) by 2025.1 Most of these predicted cases of HT are expected to occur in developing countries, which are projected to bear 75% of the global burden by 2025. Two fast-growing economies from Asia (India and China) have a huge burden of HT that is projected to increase significantly by 2025. A recent article in a prestigious Indian journal (prompted by the Chennai Urban Rural Epidemiology [CURES] study) warned that India may soon become the HT capital of the world. It already has the infamous distinction of being the diabetes capital.2 Another disturbing factor from a public health point of view concerns childhood obesity and its correlation with HT. A school health survey of 3,589 subjects aged nine, 13 and 16 years in Quebec, Canada measured BP using an oscillometric device.3 The prevalence of high, normal or elevated systolic BP was 12, 22 and 30% among nine-, 13- and 16-year-old males, respectively, and 14, 19, and 17% among females of the same ages. The prevalence of high–normal or elevated diastolic BP was <1%. Global approaches are needed to focus on lifestyle changes that may be preventative. A comprehensive population-based approach, such as that adopted by Cuba,4 is an excellent preventative model.

Brachial Blood Pressure Measurement

Reportedly, British scientist Stephen Hales was the first person to measure BP experimentally, in 1733.5 The technique for the measurement of arterial pressure using the Riva-Rocci sphygmomanometer and the Korotokov sounds has been in use for over a century, and its benefit to medicine and the care of patients has been inestimable. Recently, a greater understanding of the physiological nuances of systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and mean BP (MBP) have led to doubts about the accuracy and relevance of brachial artery BP.6

The major drawback of brachial arterial systolic BP or PP measurements is that they do not reliably represent central aortic pressure, against which the heart pumps. Although MBP remains almost constant and DBP decreases only slightly (<2mmHg) from central to peripheral vessels, the brachial artery SBP and PP may be 12 and 14mm greater, respectively, than the aortic pressure. These inconstant relationships between central aortic and brachial artery pressures are of major importance in predicting CV risk and assessing antihypertensive therapy. It is apparent that CV mortality is determined by the aortic, and not the distant, brachial BP, where most measurements are made.

Several trials7–9 have compared different drug regimens producing the same reduction of brachial SBP and DBP, but significantly different effects on left ventricular (LV) hypertrophy and/or CV mortality. These differences suggest that similar drug-induced brachial BP reduction may be associated with different central BP reduction. Angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) reduce central SBP and PP more than brachial SBP and PP. Conversely, atenolol reduces MBP and DBP with little effect on central PP. This reduced effect of beta blockades on central aortic pressure has important therapeutic consequences. The Losartan Intervention for End-point Reduction in Hypertension (LIFE) trial10 also showed similar reduction in brachial BPs with losartan and atenolol, but greater reduction in CV morbidity, mortality and LV mass with losartan. Losartan had a greater effect on central pressures than atenolol, illustrating that central PP has a more important clinical value than brachial PP.

The Conduit Artery Functional End-point (CAFÉ) trial11 showed that at similar brachial BP reductions an amlodipine regimen lowered central SBP and PP more than an atenolol regimen and was associated with improved clinical outcomes. There is increasing recognition of the limitations of the auscultatory BP method. Aortic pressures would be an improvement over brachial artery pressures, but non-invasive techniques have several disadvantages limiting their clinical utility. There is a growing body of evidence showing that ambulatory BP per se and diurnal characteristics of BP are stronger predictors of clinical outcome than clinical BP. The routine use of ABPM would be a step too far at this time, but ABPM is certainly useful in selected patients.12 Ambulatory arterial stiffness index (AASI) has been proposed as a surrogate measure of arterial stiffness and seemed to be a stronger predictor of stroke mortality than PP, especially in normotensive patients.13

Pre-hypertension – To Treat or Not To Treat?

The Joint National Committee Report on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7)14 defined a new term – ‘prehypertension’ – to refer to growing evidence that SBP values between 120 and 139mmHg and DBP values between 80 and 90mmHg are associated with increased CV risk.14 It is estimated that an additional 30% of the adult population falls into this category.15 Whether to treat the pre-hypertensive group with drugs remains uncertain, and in JNC-7 the therapeutic BP target for the general population remained at <140/90mmHg. The Comparison of Amlodipine and Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study reported the effects of normal BP, pre-hypertension and hypertension on progression of atherosclerosis.16 The most favourable rate of progression of coronary atherosclerosis was observed in patients whose BP fell within the ‘normal’ JNC category (i.e SBP <120mmHg and DBP <80mmHg). These findings suggest that achieving an SBP that is substantially below 140mmHg in patients with pre-existing coronary artery disease (CAD) is associated with a lower risk of clinical events, without any evidence of a J-curve. The study also suggests that to favourably affect the progression of atherosclerosis, decreasing the BP from a pre-hypertensive to a normotensive level may be as important as administering intensive lipid-lowering treatment. The important implication of this study is to reassess the guidelines for managing BP in patients with CAD.16,17 Perhaps what has traditionally been considered ‘normal’ BP is neither optimal nor healthy in patients with CAD.

The Trial of Preventing Hypertension (TROPHY) study18 aimed to determine whether drug treatment of pre-hypertension prevented the development of stage 1 HT. It included 809 patients with pre-hypertension (SBP 130–139mmHg, DP ≤89mmHg) who were offered lifestyle advice and randomised to treatment with candersartan 16mg daily or placebo for two years. Placebo was then given to both groups for a further two years. After a four-year follow-up there was a relative risk reduction of 15.6% (p<0.007) in the candesartan group. This study showed “that early treatment markedly retarded the elevation of BP, but this benefit was lost after treatment withdrawal”. This trial highlights the potential of therapeutic strategies in the prevention of HT progression. It was disturbing to note that lifestyle interventions were ineffective at preventing HT. In the placebo group, stage 1 HT developed in almost two-thirds of patients after four years. Despite these results, it is important to note that much of the predicted increase in the global prevalence of HT is rooted in poor lifestyle. Lifestyle interventions such as weight reduction, reduced salt intake, moderation of alcohol consumption and specialised diet should continue to be part of HT management.19

Impact of Drug Trials

In recent years, the treatment focus has moved from controlling a single risk factor to reducing overall risk. The results of the Anglo-Scandanavian Cardiac Outcomes Trial (ASCOT) lipid-lowering arm (ASCOT-LLA) clearly showed that the addition of a statin significantly reduced the risk of CHD by 36% and stroke by 27% compared with placebo.20 The ASCOT-BPLA21 was designed to answer the question of whether conventional BP-lowering therapy (atenolol ± bendroflumethiazide-K, as required) was sufficient for optimal coronary heart disease (CHD) prevention compared with a more contemporary regimen of drugs (amlodipine ± perindopril, as required). This trial was stopped earlier than anticipated (median follow-up 5.5 years) due to the clear-cut benefit of the amlodipine-based therapy on most CV end-points, total mortality (reduced by 11%) and in particular CV mortality (reduced by 24%), even though the primary end-point (fatal CHD or non-fatal myocardial infarction) was not significant.22 In ASCOT, atenolol-based therapy compared with amlodopine-based treatment reduced stroke by 23%, all-cause death by 11%, CV death by 24% and all CV events and procedures by 16%. There was also a significant 30% reduction in new-onset diabetes in favour of amlodipine-based therapy.21 The CAFÉ substudy11 showed that more effective central aortic pressure lowering with the amlodipine-based therapy resulted in reduced pulse wave reflection, indicating the importance of vasodilatation as a mechanism for optimising the reduction in central aortic pressures. These findings suggest that differential drug effects on central aortic pressure may be an important determinant of drug-related differences in clinical outcomes in trials.

The prevention of heart failure23,24 and atrial fibrillation (AF) have received attention in recent trials. In the LIFE10 trial, losartan was associated with a 33% relative risk of AF compared with atenolol. The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT)23 was a double-blind, randomised, clinical trial in 33,357 high-risk hypertensive patients aged ≥55 years and compared amlodipine, lisinopril and chlorthalidone regimens. In ALLHAT, both the primary outcomes (fatal CHD and non-fatal MI) and the most important secondary outcome (total mortality) were similar across the three groups. Davis et al.23 demonstrated the intriguing effect of these treatments on heart failure (fatal or hospitalisation).

They reported a significantly higher rate of heart failure with amlodipine (relative risk of 1.35) and a non-significantly higher rate with lisinopril (relative risk of 1.09) versus chlorthalidone. The ALLHAT results are consistent with several other studies and define a role for diuretics in preventing heart failure in high-risk patients with HT.

Another significant development has been a re-evaluation of the role of β-blockers as routine initial therapy. In addition to suboptimal stroke prevention and no definitive evidence of cardio protection,25 the LIFE10 and ASCOT trials21,22 also showed a substantially increased (25–30%) risk of diabetes with β−blockers compared with other options. The potential mechanism for their being less effective was highlighted by the ASCOT21,22 and CAFÉ11 trials. The adverse effects of β-blockers on the metabolic milieu, notably increased triglycerides, reduced high-density lipoprotein (HDL) cholesterol and impaired glycemic control, may all conspire to reduce their effectiveness in CV protection. There are a number of caveats to the anticipated demise of β-blockers, and they will continue to be used for specific indications. We will continue debating the application of these data in a younger population and, certainly, more data are needed from the newer β-blockers. Finally, a new drug, Aliskiren (a potent renin inhibitor), has been found to be safe and effective in patients with mild to moderate hypertension.26


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