The advent of a new drug is always grounds for congratulations, given the enormous odds against any one molecule. The advent of a new class is welcome in any disease, and especially welcome when there has been a 12-year gap since the last innovation – angiotensin receptor blockers in 1994. Do we need new drugs for hypertension? Resoundingly, yes! Although a combination of clear guidelines, targets and incentives has revolutionised the treatment of hypertension in primary care, the majority of patients still fail to achieve the international target for systolic blood pressure of 140 mmHg in patients without diabetes, and still fewer achieve the target of 130 mmHg in patients with diabetes.
Do we need another blocker of the renin-angiotensin-aldosterone system (RAAS)? We are about to find out! On first principles, a drug which blocks the rate-limiting step in a pathway is more effective than drugs acting downstream. Of the previously available ‘AB’ drugs that block the RAAS, angiotensin-converting enzyme (ACE) inhibitors do not achieve 100% inhibition of angiotensin II (Ang II) production because of accumulation of angiotensin I substrate. Angiotensin receptor blockers (ARBs) do achieve marked right-shifts of the dose-response curve for angiotensin. But because ARBs also block the negative feedback of Ang II upon renin, there is a several-fold increase in Ang II levels, and some variation among ARBs in their ability to block access of these to the receptor. Beta-adrenergic blockers do block the rate limiting step of the RAAS. However, reduction in heart rate increases the arterial wave reflection from a stiffened aorta, and attenuates the efficacy of beta blockers in preventing strokes.
The direct renin inhibitor aliskiren arrives at a time of recognition that most patients need multiple drugs. Essential hypertension is a hugely complex disorder, at the molecular level. The change in thinking about hypertension pathogenesis and treatment has been reflected in the phase III programme of trials for aliskiren. As well as showing this to be as least as effective on its own as comparators, many studies looked at combinations – hitherto something of a black hole in the evidence base. The privilege of having a new drug brings also responsibility to use it wisely, and it is to be hoped that direct renin inhibitors will help answer many of the big questions which remain in hypertension management. To combat ‘indolent hypertension’ we need to create confidence among practitioners in combining more effective diuresis with more effective RAAS blockade – and provide the evidence base from which the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) can achieve further dramatic improvements in the treatment of hypertension.