Thanks to everyone who contributed to the discussions about Ms Brandenberg who atended her GP for routine health screening and was found be be hypertensive. There were some great questions raised over the appropriate cut off for treatment of hypertension, and what the most appropriate first line antihypertensive would be. Some really useful links to risk calculators, NICE guidelines and online resources were highlighted by students. You can see the highlights of the Twitter discussion in the storify:
High blood pressure is the most common modifiable cause of cardiovascular morbidity and mortality worldwide, and blood pressure lowering drugs from four major classes (angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, β blockers, calcium channel blockers, and diuretics) are prescribed in large volumes. Hypertension is commonly detected in asymptomatic individuals, with treatment aimed at reducing longterm risk of cardiovascular and cerebrovascular diseases and associated morbidity and mortality. The UK NICE guidelines for investigation and management of hypertension have been recently updated, and are controversial as they are different to those from the rest of Europe and the USA (see below for further details on these differences).
1. UK NICE guidelines recommend using ambulatory blood pressure monitoring, in addition to isolated readings, to decide on whether treatment is warranted. Definitions according to NICE are:
Stage 1 hypertension: Clinic blood pressure is 140/90 mmHg or higher and subsequent ambulatory blood pressure monitoring (ABPM) daytime average or home blood pressure monitoring (HBPM) average blood pressure is 135/85 mmHg or higher.
Stage 2 hypertension: Clinic blood pressure is 160/100 mmHg or higher and subsequent ABPM daytime average or HBPM average blood pressure is 150/95 mmHg or higher.
Severe hypertension: Clinic systolic blood pressure is 180 mmHg or higher, or clinic diastolic blood
pressure is 110 mmHg or higher.
2. The blood pressure reading is not the only important factor – the key is to risk stratify patients. The decision to initiate a patient who is otherwise “well” on medications that are likely to continue lifelong (with their possible side-effects) is not trivial. The risk-benefit assessment is based on the degree of their hypertension, the presence of end-organ damage (implying that the patient has already sustained injury from high blood pressure, and predictive that continued hypertension will cause further deterioration and morbidity), and the overall cardiovascular risk. NICE recommends that antihypertensive treatment should be offered to people under 80 years with stage 1 hypertension who also have: target organ damage; established cardiovascular disease; renal disease; diabetes; a 10-year cardiovascular risk equivalent to 20% or greater (using Framingham).
3. The selection of an antihypertensive is based on which is most likely to be effective, with knowledge gained from primary research including large randomised control trials (a list of landmark trials is available from the University of Minnesota). NICE recommends that you offer people aged under 55 years an ACE inhibitor or a low-cost ARB. Offer people aged over 55 years and black people of African or Caribbean family origin of any age a calcium-channel blocker (CCB). If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic
4. Pharmacological treatment must not be given in isolation. Lifestyle interventions and patient education are essential components of risk modification.
- NICE Guidelines on hypertension (CG127)
- Summary of new NICE Guidelines in the BMJ
- Cardiovascular risk calculator from The University of Edinburgh based on Framingham data
- European Society of Hypertension guidelines: Perk et al (2012) Eur Heart J
- Paper: Optimisation of antihypertensive treatment by crossover rotation of four major classes.
The Lancet – 12 June 1999 Vol. 353, Issue 9169, Pages 2008-2013
- Paper: Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. Journal of Hypertension. April 2002 – Volume 20 – Issue 4 – pp 771-777.
- Videos from the British Society of Hypertension discussing guidelines and treatment
- Critical reviews of recent NICE guidelines:
i) McManus et al (2012) NICE hypertension guideline 2011: evidence based evolution. BMJ 344:e181 – the authors of this review respond to criticisms of the 2011 NICE guideline, arguing that it reflects the reduced costs of generic drugs and new evidence on cardiovascular risk reduction
ii) Sofat et al (2012) Could NICE guidance on the choice of blood pressure lowering drugs be simplied? BMJ 344:d8078 – this is a really useful review article that looks at many of the well-known trials in the field and questions the NICE guidelines’ emphasis of the differences between different classes of antihypertensives. They argue that evidence indicates that the four classes of drug are more similar than different in their clinical efficacy and safety and that their effects in combination are additive, irrespective of mechanism. The initial choice of drug class and combination could thus rest on price, tolerability, and specific contraindications in individual patients. The authors believe that this simplification would benefit healthcare commissioners, doctors, and patients.
Dr Daniel Marks, Clinical Pharmacologist at UCLH and Wellcome Postdoctoral Research Fellow in Molecular Medicine says:
There were some great discussions on this interesting dilemma.
Our patient Ms Brandenberg has stage I hypertension, as defined by their ambulatory blood pressure monitoring (ABPM) reading. Note that the thresholds with ABPM are 5 mmHg lower than those using clinic BP. She has no evidence of end-organ damage, but the lipid profile (specifically the total cholesterol:HDL ratio, which can be calculated from the data provided) confers a 10-year cardiovascular risk in excess of 20%. Although lifestyle changes should be recommended, pharmacological therapy for hypertension should also be offered. The suggestion for co-prescription of a statin is very sensible. Many doctors would also provide aspirin, although there is less evidence for its efficacy in primary prevention of vascular events in women than in men.
The current NICE guidelines advocate different first-line anti-hypertensive therapies on the basis of patient age and ethnicity:
- an ACE inhibitor or angiotensin receptor blocker in young Caucasian patients
- calcium channel blockers in everyone else
This is based on the premise that the former have “high renin”-driven hypertension, whereas activation of the renin-angiotensin-aldosterone system is less pronounced in the latter. Ms Brandenberg is on the cusp of both categories (being exactly 55 years old, and of half-European half-Caribbean descent). A pragmatic solution, working within these guidelines, would be to start a calcium channel blocker, as she will be over the age of 55 for almost all of her treatment.
Nonetheless, it is important to recognise that these NICE guidelines are controversial, with supporters and detractors both within the UK and abroad. Indeed, the current European and American guidelines for hypertension differ significantly. The two principal points of contention are the routine use of ABPM for diagnosing hypertension, and the choice of first-line anti-hypertensive agent.
The most recent NICE guidelines advised a switch from the traditional method of using three separate clinic readings to diagnose hypertension, to use of ABPM following a single high clinic reading. This was based on their analysis of a large number of studies (albeit of varying quality), and of its estimated cost-effectiveness.
However, several assumptions were required to arrive at the conclusions reached. The key ones are that:
i) Treating patients based on ABPM readings is superior to treatment based on clinic blood pressure readings. It is important to realise that no intervention trials in hypertension have enrolled and randomised subjects on the basis of ABPM. The wealth of clinical trial data that demonstrates the morbidity and mortality benefits from treatment of high blood pressure is derived almost in its entirety from patients diagnosed using traditional clinic readings. In fact, many studies (such as the PAMELA trial), that examined for benefits of use of ABPM over clinic readings found no evidence of superiority.
ii) The treatment threshold of 135/85 mmHg with ABPM is derived using an “equivalence” approach. This consists of using observational data to correlate the average daytime blood pressure values that correspond to a clinic blood pressure reading of 140/90 mmHg. This is not the same as evidence derived from a clinical trial directly designed to treat hypertension based upon this ABPM threshold, and hence equivalence of treatment effect cannot be automatically assumed.
iii) ABPM provides a considerable amount of information, and it is not yet clear how to use this. At present, treatment recommendations are based on the mean blood pressure. However, data can also be extracted regarding the peak values, proportion of blood pressure readings above certain thresholds, nocturnal versus daytime blood pressures, and overall blood pressure variability. No-one yet knows how to incorporate these factors into risk assessments and treatment recommendations.
The other principal area of contention relates to drug choice, and specifically whether this should differ in younger and older patients, and whether thiazide/thiazide-like diuretics and beta-blockers are justly relegated to third and fourth line agents.
The objections to this approach are that:
i) The NICE statement that ACE inhibitors and angiotensin receptor blockers are more effective in younger people than calcium channel blockers and thiazides derives from: (1) two studies of hypertensive patients younger than 55 years, which recruited small samples; (2) a single larger study that identified no statistically significant differences in outcomes between a number of anti-hypertensive drug classes in patients above or below 60 years of age; and (3) a personal communication from the authors of the ASCOT trial (but without provision of any accompanying data in the guideline document).
ii) Conversely, a very large meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration (which included >190,000 patients followed up prospectively for many years) found no difference in blood pressure lowering or outcome reduction ability between any drug classes in patients older or younger than 65 years.
iii) NICE cite the ALLHAT, ASCOT and VALUE trials in support of their contention that calcium channel blockers and thiazide/thiazide-like diuretics exert a greater blood pressure lowering effect in older patients. However, the mean age of patients in ALLHAT was only 67 years, and in ASCOT only 63 years; these are therefore not broadly representative of older patients being treated in routine practice. Furthermore, in ASCOT, the majority of patients labelled as deriving greater benefit on calcium channel blockers were actually on combined treatment that included an ACE inhibitor. Additionally, in VALUE, there was a subgroup analysis that showed no significant differences in treatment effects between drug classes in patients above and below the age of 65. NICE also does not reference trials such as STOP-HY2 (that studied patients older than 70 years, in which outcomes were the same between ACE inhibitors and calcium channel blockers), nor SCOPE or ANBP-2 (in which ACE inhibitors were superior).
iv) Finally, the NICE meta-analysis on which the downgrading of thiazides and beta-blockers is based differs in its conclusions from the findings of others groups and bodies. Although NICE used rigorous selection criteria for trial quality, they still included small trials with low outcome frequencies while omitting other larger trials, and this did impact on interpretation. More importantly, NICE did not take into account differences in blood pressure lowering actually achieved in the various trials, which did differ in many between alternative treatment regimens. Put another way, the NICE recommendations are based on an analysis that does not directly relate the anti-hypertensive class to the magnitude of its blood pressure lowering effects. If there are any real differences between calcium channel blockers, diuretics and beta-blockers, these are subtle at best, and may disappear if sufficient doses of the latter two agents are used to achieve the same blood pressure lowering effect. There may furthermore in some patients be additional benefits to using drugs such as beta-blockers if they have concomitant diagnoses such as atrial fibrillation or cardiac failure.
How does one then proceed based on the above? Overall, the NICE recommendations are based on evidence, but their conclusions incorporate a substantial amount of opinion. This does not mean that they are wrong, but that doctors using any guidelines should be aware of what is evidence-based and what is not. If I were reviewing this patient in clinic, I would certainly recommend starting anti-hypertensive drug therapy based on her overall level of cardiovascular risk. However, it would probably be reasonable to offer an agent from any of the four main classes, with inexpensive drugs being more cost-effective than more costly agents. As these are drugs that patients may have to take for life (and non-concordance with medication is a huge problem in hypertension management), I would try to spend some time counselling the patient and discussing the potential side-effect profiles. I would then prescribe the drug they thought they would tolerate best, and offer early review with the option to switch agent should limiting side-effects occur.