Guidelines for blood pressure detection and treatment are very much creatures of the medical model of healthcare in that they are concerned with patients (at personal high absolute risk) and doctors (who detect and reduce that risk). In this context, guidelines provide a framework that supports medical decision-making for diagnosis, investigation and treatment. Time is precious for busy practitioners and to make things simple, guidelines define levels of blood pressure for intervention (essentially diagnostic thresholds) and the goals of treatment.
The blood pressure targets have developed largely on the back of clinical trials. For example, in the early days, systolic blood pressure was largely ignored and trials addressed diastolic pressure 1. Consequently, guidelines such as JNC1 from 1977 followed suit, with diastolic targets alone 2.
The early trials tackled relatively high blood pressures using a limited number of drugs 1. There was real (but unnecessary) concern that treatment might compromise the perfusion of key organs. With success came confidence to examine the potential additional benefit of starting at and/or aiming for lower blood pressures. New trials also considered the possible relative advantages of different drug classes. This was the age of trials in ‘mild hypertension’ facilitated by the development of newer, more effective and safer therapies. As a result, thresholds and targets for treatment tended to come down. However, this golden era of cardiovascular pharmacology had its problems.
It might be hard to imagine in the contemporary environment, but the early hypertension trials in the 1960s and 1970s were placebo controlled, which today would not be ethical 1,3. They provided relative clarity on the effect of certain treatments. Furthermore, higher blood pressures meant correspondingly high risks of coronary disease and stroke. This offered statistical power that provided confidence in treatment benefits with relatively small number (hundreds) of participants.
As lower pressures were addressed, the theoretical increment in the benefit of treatment also diminished according to the epidemiological log-linear relationship between blood pressure and cardiovascular risk. In otherwise healthy individuals with relatively modest elevations in pressure, the personal risk of treatment threatened to overtake the risk of the blood pressure per se. In addition, modern trials found themselves operating at the margins of potential benefit, sapping them of statistical power to show the smaller and smaller effects on cardiovascular risk. This situation has been exacerbated by the underlying decrease in the community-wide risk of cardiovascular disease. Whether or not this reflects better lifestyles, better detection or better treatments (including the ubiquitous statins 4) is unclear, but it reduced the trial endpoints. As a consequence, it has meant that modern trials must be large (frequently around 10 000 participants), long (often 5 years) and expensive. What is more frustrating is that clear-cut cause and effect relationships are often obscured by the lack of placebo controls and confounded by other cardiovascular risk-reduction treatments. This has generated uncertainties in the interpretation of trials and creates room for debate in guidelines.
Just when we need certainty from new large blood pressure trials, they are drying up. Unless the government is prepared to step in, what drug company would want to invest perhaps $100 million or more to test a drug with no, or limited, patent life over many years to show a small effect with equivocal confidence?
Where does this leave hypertension guidelines? The inevitable result of a lack of significant new trial data is that more recent guidelines are raking over the old data in search of some new insights and interpretations. The dialogue still centres on specific blood pressure levels as treatment goals and, somewhat surprisingly, new conclusions are emerging.
The recent backpedalling on the treatment goals for blood pressure in those with pre-existing cardiovascular disease, diabetes or renal disease 5 has been a hot topic 6. Just when practitioners were warming to the idea that the background increase in cardiovascular risk that accompanies these conditions justifies a more intensive approach to blood pressure reduction, they are informed by influential guidelines that they should revert to a treatment goal of 140/90 mmHg and that the previous recommendation of 130/85 mmHg is too low 5, not because there is clear evidence of damage, but because there was no unequivocal evidence of benefit. The latter arose in part through lack of suitable trials or inadequate statistical power in existing trials.
A disappointing aspect is that the continuing debates and opinions about targets seem to have distracted guidelines from acknowledging and considering other effective treatment paradigms that do not rely on targets. These paradigms share more with the public health model in which an intervention is applied broadly to achieve small effects for individuals that accumulate to a large benefit across the treated population.
In the world of cardiovascular medicine, we are familiar with safe, effective and cheap public health advice on diet and lifestyle. However, pharmacotherapy in the public health model is less familiar. Yet, aspirin is not a bad example. Aspirin (which is freely available over the counter in most countries) is recommended for cardiovascular prevention. It is usually taken without knowing about the pre-existing clotting tendency and without measurement of its effect on bleeding time 7. It is accepted that the relative benefits for the vast numbers on aspirin will outweigh the risks. In the medical setting, we tip the scales towards benefit by using aspirin where there is a higher than average cardiovascular risk, such as those with a transient ischaemic attack or previous stroke or those with coronary disease.
Lurking in the blood pressure guidelines is a new breed of trials that mirror the aspirin example. These trials include HOPE 8, PROGRESS 9 and ADVANCE 10. Their common feature is that they administered antihypertensive drugs to hypertensive and normotensive individuals and without regard to a specified target. This is sometimes referred to as the ‘routine’ blood pressure-reduction paradigm. As shown in Fig. 1, it results in a relatively small reduction in blood pressure in all individuals as opposed to potentially larger reductions in a few in the traditional medical approach.
The routine treatment paradigm meant that the trials included large numbers of individuals without hypertension who would not normally receive blood pressure-lowering drugs. However, all participants in HOPE, PROGRESS and ADVANCE were at increased cardiovascular risk as a result of other factors such as coronary disease, stroke, diabetes, etc. The notion was that a modest reduction in blood pressure (which is almost impossible to identify in individuals) in those (hypertensive or not) with high cardiovascular risk would reduce this risk.
The hypothesis was that the accumulation of relatively small reductions in individual risks would result in an overall benefit in the treated population, and indeed this was true, and included benefits for undeniable and critical end points such as death 8–10.
Yet, almost without exception, existing blood pressure guidelines view these trials through the lens of targets. Most often, the achieved average pressures in the actively treated groups are portrayed as if they were a priori blood pressure targets. The fact that these trials included a considerable proportion of participants with baseline normal blood pressures is lost in such considerations. For example, it is inappropriate to deem the achieved average systolic pressure of 136 mmHg in the ADVANCE trial 10 as a target, given that a large proportion (perhaps one-third) of the participants entered the trial with a pressure below that level. Nobody would suggest that the goal in these participants was to increase blood pressure.
It would be refreshing if guidelines were able to look beyond the blood pressure target model and start to come to grips with the routine blood pressure reduction treatment approach.
This is especially relevant for patients with pre-existing cardiovascular and renal disease and diabetes. At the moment, there is a discrepancy in that guidelines are recommending against lowering blood pressure below 140/90 mmHg and the results of HOPE, PROGRESS and ADVANCE recommend such treatment. This needs to be reconciled for the benefits of patients.
Guidelines are not providing the green light to the treatment of lower levels of blood pressure as in these trials because analyses (with inadequate statistical power) are carried out in post-hoc subgroups in which the clinical benefits, although entirely consistent with the overall trial outcomes, are not statistically significant.
Those holding out for even larger trials to achieve the necessary statistical power to resolve this discrepancy are likely to be disappointed for the reasons discussed above. In their absence, it becomes a choice between an error of commission (to treat) and an error of omission (not to treat). Should we deny patients a safe and effective treatment approach with overall benefits because irregular subgroup analyses cannot show watertight significance?
This might not be easily resolved, but at least the guidelines should appreciate the existence of the routine treatment approach in high-risk patients and consider the model as intended.
Interestingly, other guidelines for cholesterol have re-examined existing trial data and concluded that targets should be dropped in favour of a more routine approach on the basis of cardiovascular risk 11.
The 2013 ACC/AHA cholesterol guidelines have been described as a ‘paradigm shift’ and have moved away from cholesterol targets as the primary mission. Instead, management depends first on the determination of atherosclerotic cardiovascular disease risk, for which a new calculator has been introduced. This is used to identify groups of patients who are most likely to benefit from cholesterol treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). The intensity of the statin therapy is directly proportional to the degree of risk. High-intensity statin therapy is expected to reduce low-density liporoprotein cholesterol by ∼50% and moderate-intensity statin by 30–50% from baseline. There is no advice to titrate statins to achieve a target cholesterol level. There has been debate on aspects of these guidelines 12, but they have been hailed as ‘a major step in the right direction’ 13.
If one major cardiovascular risk factor treatment guideline can take this step beyond targets, will others follow? It is hard to imagine blood pressure guidelines adopting such a unitary approach. After all blood pressure has a more complex portfolio of causes and complications, it is inherently more variable and treatment options are more extensive. There is unlikely to be a wholesale shift from blood pressure targets to routine treatment. Indeed, the HOPE, PROGRESS and ADVANCE trial incorporated targeted treatment of hypertension as background management at the discretion of the treating physicians. Nevertheless, it is almost inevitable that the concept of routine blood pressure treatment in high-risk individuals will appear more deliberately in blood pressure guidelines of the future and guide physicians towards new means of improving the cardiovascular risk of their patients.
Blood pressure treatment paradigms can be targeted in hypertensive individuals towards recommended goals or given routinely to all individuals independent of blood pressure. The two approaches can be complementary.
Conflicts of interest
The author has received honoraria for speaking from Servier, Novartis and Daiichi-Sankyo.
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