Treating hypertension

There are many different drug classes available for the treatment of hypertension and new classes continue to emerge. This has been fertile ground for drug development as pharmaceutical companies compete for a much coveted recommendation as an appropriate ‘first line or initial therapy’ for hypertension. This debate has been energized by the recent publication of ALLHAT [1]. ALLHAT was designed to determine the effectiveness of initial therapy with newer blood pressure lowering drugs at reducing a primary endpoint of fatal coronary heart disease (CHD) or non-fatal myocardial infarction compared to older therapy, as represented by the thiazide diuretic chlorthalidone. The primary outcome occurred in 2956 participants and there were no differences between the rates with the reference drug chlorthalidone (11.5%) compared to amlodipine (11.3%) or lisinopril (11.4%). Moreover, this conclusion was valid irrespective of the patient's sex, ethnicity or diabetes status [1]. ALLHAT provided an important but null result, thereby suggesting that the three drug classes were as effective as each other in reducing the primary endpoint when used as initial therapy for the treatment of hypertension. It was surprising therefore that the perception gained from subsequent publicity and the accompanying editorial in the JAMA was that the thiazide was ‘the winner’ and that newer drugs could be dismissed as no more effective, more expensive and thus irrelevant to the modern treatment of hypertension [1,2]. Moreover, this conclusion was generalized to all people with stage 1 or 2 hypertension [1,2]. In addition, it was concluded that the increased risk of developing type 2 diabetes, hypokalaemia and hypercholesterolaemia with thiazide therapy was unimportant because this did not adversely affect outcome [1,2]. These bold statements are worthy of closer scrutiny. No sensible physician would dispute the fact that the thiazide diuretics are a proven and very effective treatment for hypertension, especially in older people such as those studied in ALLHAT. ALLHAT was not necessary to confirm that. However, in the absence of any data, it is not appropriate to generalize this conclusion to younger patients in whom blockade of the renin–angiotensin system (RAS) either with β-blocker, angiotensin-converting enzyme (ACE)-inhibitor or angiotensin II antagonist, is likely to be more effective at lowering blood pressure than a thiazide diuretic [3]. ALLHAT was designed to evaluate ‘initial therapy'. The subsequent publicity surrounding the presentation and publication of the results of this trial conveyed the impression that the thiazides alone were so remarkably effective a treatment that little else was necessary. This could not be further from the truth. All clinical trials of blood pressure lowering therapy have confirmed that combinations of drugs are required to lower blood pressure towards recommended targets. In almost all trials, these targets have not been achieved in the majority of patients, especially for systolic blood pressure [4]. This was also confirmed by ALLHAT which showed that 63% of patients required two or more drugs to control blood pressure to less than 140/90 mmHg. Moreover, blood pressure control was more difficult in those at highest risk (i.e. older patients, those with highest systolic blood pressure at baseline, Black patients or diabetics), who generally required more than two drugs. Thus, ALLHAT was not a trial of monotherapy, nor did it end up as a trial of initial therapy because, in the end, most patients received additional blood pressure lowering drugs. This cannot be considered irrelevant to the outcome. Put simply, the treatment of hypertension is less about which drug you start with and more about which combination of drugs most effectively controls blood pressure to target. Accepting that combinations of blood pressure lowering drugs will be required for most patients, the weight of evidence from ALLHAT and all previous trials strongly supports the conclusion that a thiazide diuretic should form part of this treatment cocktail. However, ALLHAT does not inform about the ideal or optimal drug combination. By contrast, by trying to initially study four different first line comparisons (chlorthalidone versus amlodipine, doxazosin or lisinopril), ALLHAT ran out of options for second line therapy for those uncontrolled on monotherapy. This inevitably led to some unconventional, if not illogical, drug combinations that favoured the diuretic arm of the trial. The most common add-on therapy in ALLHAT was a β-blocker. This is a logical addition to a thiazide where the renin-inhibiting actions of β-blockade would be expected to synergize with the RAS activating actions of a thiazide. This contrasts with the less logical addition of a β-blocker to an ACE-inhibitor which would be expected to be much less effective at lowering blood pressure in older patients, and especially Blacks. This was confirmed by ALLHAT: blood pressure control in the ACE-inhibitor arm was less good at every time point recorded compared to the thiazide diuretic, especially in Blacks. It cannot be concluded that the nature of the drugs used in combination to treat hypertension is irrelevant to blood pressure lowering efficacy or outcome. Nor should the worshipers at the ALLHAT temple dismiss newer therapies as an unimportant component of combination therapy. Current evidence, including that from ALLHAT, does not exclude the possibility that the combination of a thiazide with a newer drug, would be more effective than the combination of a thiazide with older drugs such as a β-blocker. There have been too few trials comparing balanced combinations of drugs. The recent data from the LIFE study fulfils this criteria and strongly supports the hypothesis that the types of drugs used in combination can influence cardiovascular outcome in people with hypertension [5]. LIFE compared losartan-based therapy with atenolol-based therapy in people with hypertension and ECG-left ventricular hypertrophy. Almost all patients in LIFE (> 90%) received a thiazide diuretic in both arms of the trial. Thus LIFE was a trial of ‘older therapy + thiazide’ versus ‘newer therapy + thiazide'. There was clearly a superior outcome with the ‘newer therapy/thiazide’ combination, especially with regard to stroke prevention [5]. Whereas ALLHAT might rightly conclude that it does not matter what drug you use to initiate therapy, and thus why not use a thiazide, it is wrong to conclude that the addition of further drugs to the treatment cocktail would not influence outcome. Dyslipidaemia, hypokalaemia and new onset diabetes were more common in patients randomized to chlorthalidone compared to amlodipine or ACE-inhibition [1]. The authors of the ALLHAT report in the JAMA, and the accompanying editorial, implied that these potentially important adverse effects of thiazide β-blocker therapy were less important than previously suggested because there was no detrimental effect on cardiovascular outcome [1,2]. Such a dismissal is alarming, ill-considered and unfortunate. ALLHAT was a trial conducted over 5 years whereas most people are treated for hypertension for many more years. It is inconceivable that the induction of diabetes in a patient with hypertension would not, over the longer term, lead to a substantial increase in cardiovascular risk and microvascular complications, not to mention premature death [6]. Diabetes is reaching epidemic proportions in Westernised societies and hypertension and diabetes is a lethal duet [6–9]. Moreover, hypertension per se is associated with a doubling of risk of developing type 2 diabetes [10]. Previous studies have suggested that newer drugs (often in combination with a thiazide) are associated with a significantly reduced likelihood of developing type 2 diabetes in people treated for hypertension compared to people treated with older drugs, especially a β-blocker/thiazide combination [5,11]. This observation once again highlights the fact that that the nature of the drug combination is important, and a more important consideration than the initial therapy. Finally, if we accept that the debate about initial therapy for hypertension will inevitably continue, perhaps we can at least move the debate into new territory. If drugs are so poor at achieving target in monotherapy, why do we persist with single drug therapy for hypertension? If combinations of drugs are likely to be required by most people, why must the debate continue to focus on single drug entities as initial therapy? Surely the time has come to consider and evaluate the use of a fixed dose combination therapy, which includes a diuretic, as initial therapy for people with hypertension, especially those in whom systolic blood pressure is difficult to control (i.e. older patients, people with isolated systolic hypertension and people with diabetes). Such an approach is likely to result in a more consistent blood pressure lowering response across a wide age range and improved blood pressure control. ALLHAT was an important study but ALLHAT is not the final word. It asked a question about the beginning of treatment and the beginning does not appear to matter. What matters is the end: defining the combination of drugs that most efficiently optimizes blood pressure control and reduces cardiovascular risk over the longer term, with minimal adverse effects [12].