CVS

د. حسين محمد جمعه

اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Controversies over hypertension guidelines

BMJ 25 January 2012

The proper management of hypertension is arguably one of modern medicine’s most effective preventive interventions. It’s also one for which we have lots of clinical trial data, as well as a good number of well done meta-analyses.
Yet as this week’s BMJ shows, controversy about how best to diagnose and treat hypertension in adults is still alive and well.

The 2011 guidance from the UK’s National Institute for Health and Clinical Excellence (NICE) has been met with a blast of criticism. This week we present two different critiques: the first suggesting that the guidelines are overcomplicated, the second
that they are insufficiently evidence based. In a third article, the guidelines’ authors respond.

What did the 2011 update say? It was, in fact only a partial update, focusing on areas where the evidence was deemed to have moved on since 2006. But it made several key changes to previous guidance. These included advice to use ambulatory and home blood pressure monitoring to confirm a raised clinic
reading, and a different choice of drug class for first and second line treatment.


In place of the well established AB/CD algorithm—angiotensin converting enzyme inhibitor or β
blockers/calcium channel antagonist or diuretic—the updated guidance recommends ACD in people under 55: ACE inhibitor or angiotensin II receptor blocker, followed by a calcium channel blocker, followed by a thiazide-like diuretic.

Patients over 55 are recommended to start on a calcium channel blocker.

Reecha Sofat and colleagues think this is overcomplicated (doi:10.1136/bmj.d8078).
The most recent evidence suggests that the four drug classes are more similar than different in their
efficacy and safety, they say, and that their effects in combination are additive.
This means that the initial choice of drug could rest on price, tolerability, and individual patients’characteristics.

Morris Brown and colleagues take a different tack (doi:10.1136/bmj.d8218). They say there are no outcome data from trials that justify the shift to ambulatory and home monitoring, and they
are surprised by NICE’s conclusion that ambulatory monitoring could cut the number of people starting on antihypertensive drugs by a quarter.

“The combination of a rise, compared to previous guidance, in the blood pressure threshold for treatment and a longer interval before repeat monitoring is not plausible,evidence based, or safe,” they say. They are equally concerned about the relegation of diuretics from first to third line treatment, and the recommendation to use chlortalidone, for which no suitable 12.5 mg formulation is available in the UK.

“The combination of a rise, compared to previous guidance, in the blood pressure threshold for treatment
and a longer interval before repeat monitoring is not plausible, evidence based, or safe,” they say.
They are equally concerned about the relegation of diuretics from first to third line treatment, and the recommendation to use chlortalidone, for which no suitable 12.5 mg formulation is available in the UK.

Good cheap drugs such as co-amilozide are overlooked, they say.

In reply, the guideline’s authors argue convincingly that the recommendations are evidence based and that this latest guidance is an evolution that will continue as more evidence accrues (doi:10.1136/bmj.e181). Both sets of critics say that,
despite the many trials and meta-analyses already done, a great many questions remain.


Brown and colleagues try to make the best of what they clearly see as a bad job in calling for the latest
NICE guidelines to serve as a catalyst for more robust clinical trials. Sofat and colleagues call for an updated network meta-analysis, taking into account the evidence from recent large influential trials and meta-analyses.

NICE hypertension guideline 2011: evidence based evolution

BMJ 13 January 2012

The two articles criticising some of the recommendations in the recent National Institute for Health and Clinical Excellence (NICE) hypertension guidelines1 2 come from different, and sometimes contradictory, standpoints.
We discuss the process undertaken in developing the recommendations and respond to the points raised.

NICE guideline development process

NICE guidelines are developed through a standardised, rigorous, and transparent method. It starts with the development of a series of questions (the “scope” of the guideline) and setting up a guideline development group with representatives from key stakeholders (typically patient and carer representatives, experts, nurses, general practitioners and a chair or clinical lead, all of whom are appointed after public advertisement), a project manager, and a technical team, with representatives from NICE and other experts sitting in as necessary.

There is then a detailed search for efficacy and cost effectiveness literature; where required, technical staff do new meta-analyses and economic
modelling. The process is open with minutes of all group meetings freely available (http://guidance.nice.org.uk/CG/Wave2/14/Development/GDGMinutes for Hypertension), and
there is an extensive and exhaustive process of external consultation for each guideline.

This includes detailed consideration of the scope and publication of a draft guideline before the guideline emerges in its final form. All responses to
the consultation are collated and responded to individually, and an audit process ensures that difficult questions are not ignored.
Groups such as specialist societies, commercial organisations,research groups with a particular interest, and hospital trusts can register as stakeholders and provide detailed comments.

In the case of hypertension, the update was partial, which meant that the scope was limited to areas where it was considered that the evidence had moved on since the last guideline in 2006. The underlying model for the guideline remained the detection and treatment of individuals with uncomplicated primary hypertension, whose blood pressure remains persistently raised above internationally recognised blood pressure thresholds.


Diagnosis of hypertension
The 2011 guideline continued the risk based approach to diagnosis and starting treatment first proposed by the New Zealand guidelines in 1993 and included in subsequent British Hypertension Society and NICE guidelines since 1999.

The method for diagnosing hypertension was refined after review of evidence from 19 studies considering the relative prognostic ability of ambulatory or home blood pressure monitoring (ABPM and HBPM respectively) compared with clinic
monitoring in determining outcome on the basis of baseline blood pressure.

These studies showed that “out of office measures” are better than clinic measurement at predicting
subsequent risk of cardiovascular events and many, including the PAMELA study, were included in Fagard and Cornelissen’s 2007 meta-analysis.8 This showed a hazard ratio for cardiovascular events of 1.12 (95% confidence interval 0.84 to 1.50) for “normal” ambulatory blood pressure with “raised” clinic measurements (white coat hypertension) compared with “normal” ambulatory and clinic pressures (definitively normotension).

Included studies had follow-up periods of between 3.2 and 10.9 years (only one was less than five years)
suggesting no evidence of increased risk from white coat hypertension over and above normotension over a standard five yearly screening cycle. This provided the rationale for the recommendations on diagnosis, not a belief that hypertension is currently “over treated” as Brown and colleagues claim.

These data, combined with a new meta-analysis showing the relative test performance of clinic and home measurement,triggered the development of an economic mode. This showed that ambulatory monitoring was the dominant strategy for the diagnosis of hypertension for both men and women in all age groups from 40-75 years and that this conclusion was robust to
a wide variety of sensitivity analyses.

Exceptions to this were if normotensive people were assumed to benefit from blood pressure reduction or if the test performance of all three monitoring methods was considered equal. An absence of trials of the “polypill” approach as well as evidence from the systematic review of test performance in diagnosis meant that these analyses were not considered sufficient to overturn the main results.

If re-testing of all screened individuals took place annually rather than five yearly, ambulatory monitoring was cost effective for people older than 60 but not younger. This scenario was deemed extreme as only people around the diagnostic threshold are likely to need frequent retesting, hence ambulatory monitoring retained its
dominance. The guideline therefore recommended at least five yearly screening but annually for those close to the threshold.

Ambulatory blood pressure thresholds

The thresholds for normal ambulatory blood pressure, unchanged from NICE guidelines since 2004, were not based on a single study but were supported by the results of the prognostic meta-analysis and are consistent with international recommendations. Head and colleagues’ paper supports the
appropriateness of the ambulatory equivalents to clinic measurements, particularly for the stage 1 and 2 thresholds.Guideline targets are based on mean achieved blood pressure as well as targets in trials, hence mean blood pressure comparisons are relevant.


General considerations for choice of drugs
The general argument put forward by Sofat and colleagues that choice of antihypertensive drug should rest on cost, tolerability,and specific contraindications, ignores efficacy at preventing morbid and mortal cardiovascular events, which the guidelines considered to be most important. Cost is now much less relevant as the main classes are available as generic drugs at broadly equivalent prices.
The 2011 guidance aimed to recommend the most cost effective drugs, taking into account tolerability and most conceivable specific indications.

First line treatment

The other major area where changes were implemented in the 2011 guidelines was in treatment choice. Here again, the
guideline development process was dictated by cost effectiveness. The 2006 model critiqued by Sofat and colleagues was updated to take account of the reduced costs of drugs as all are now available as generics.

Importantly, the model showed that treating hypertension is cost saving versus no treatment.
As in 2006, calcium channel blockers emerged as the most cost effective option but now more so because of their availability as generic formulations. This was the principal driver for recommending calcium channel blockers as the preferred initial therapy for most people over the age of 55 years, the exception being people with evidence of heart failure or at higher risk of heart failure, for whom the sensitivity analysis suggested athiazide-like diuretic should be preferred as initial therapy.

That calcium channel blockers are also less likely to cause impaired glucose tolerance, electrolyte disturbances, and gout and have been reported to be particularly effective at reducing blood pressure variability (which has recently been suggested as an independent predictor of risk, especially for stroke) further strengthened the rationale for this recommendation.

Another consideration was that the only trial to directly evaluate two drug combinations of treatments with a renin-angiotensin receptor system blocker, consistent with step two of the NICE
treatment algorithm, also showed that combination with acalcium channel blocker was better than with a thiazide diuretic for preventing cardiovascular outcomes.

The differentiation of drug choice for initial treatment according to age was maintained because sensitivity analyses showed that even small advantages in efficacy for drugs blocking the renin-angiotensin system over other classes made angiotensin converting enzyme inhibitors and low cost angiotensin receptor
blockers very cost effective in younger people.

Diabetes, like hypertension, relies on an arbitrary cut-off for diagnosis, but why would somebody want to develop diabetes if it could be
avoided? The hazard ratio in the ASCOT trial for development of diabetes was 0.70 (95% CI 0.63 to 0.78) for calcium channel blocker plus angiotensin converting enzyme inhibitor arm
compared with β blocker plus thiazide.


Sarwar and colleagues’ outcome data show that diabetes is associated with increased
hazard ratios for coronary heart disease of 2.00 (95% confidence interval 1.83 to 2.19) and 2.27 (1.95 to 2.65) for ischaemic stroke.16 The NICE model assumed a doubling of cardiovascular
risk with diabetes in the base case, but at all levels of risk from diabetes calcium channel blockers remained the most cost effective option, even if the relative risk of cardiovascular events with diabetes was set to 1 (that is, no increase in risk of events).

Choice of diuretic

Another question in the scope related to the choice of diuretic.
The United Kingdom is unique in the world in its almost
exclusive use of lower dose bendroflumethiazide (usually 2.5 mg once daily) to treat hypertension. The evidence review found no data evaluating and supporting effectiveness of this treatment in preventing cardiovascular events.

It was therefore difficult to continue to recommend it. More contemporary studies had

used thiazide-like diuretics (chlortalidone and indapamide). The evidence for these drugs at modern doses was substantial,
including several large primary prevention trials such as SHEP,ALLHAT, and HYVET.18-2

Both are also available as low cost generic formulations and the decision, based on best available evidence, was that these should be the preferred diuretics.
Although chlortalidone is available in the UK only in higher doses (50 mg), it should not stretch the organisational capability of the NHS to respond because the recommended doses are widely available elsewhere.

β blockers

In the updated meta-analysis for this guideline, as in previously published independent meta-analyses, β blockers were the least cost effective treatment for hypertension and notably less effective than the recommended first line drugs. Law and
colleagues’ meta-analysis also found them to be significantly worse at preventing stroke than other drugs (relative risk 1.18 (1.03 to 1.36)).

This may be a function of β blockers inferiority

to calcium channel blockers or of less effective blood pressure reduction, but whatever the cause it is difficult to ignore when making recommendations for treating hypertension.


Fourth line treatment for resistant
hypertension
The evidence for fourth line treatment options in hypertension is currently suboptimal. However, people with treatment resistant hypertension are a high risk group and the evidence, albeit primarily from six observational studies, suggested that low dose spironolactone can be very effective at further reducing
blood pressure.

This strategy is common practice in specialist

hypertension clinics. Consequently, the 2011 guideline gave a“steer” towards the use of low dose spironolactone, while making clear in the research recommendations that more definitive evidence is needed. The ongoing PATHWAY studies
will hopefully provide clarity in this area.

Conclusions

Finally, although we welcome healthy academic debate about the finer detail of the guideline, the key to its success is buy-in from clinicians. To date this has been high, at least in part because of the continued support of the British Hypertension Society, which has made a series of videos covering key aspects
of the guidance (www.bhsoc.org/stream/BHS_Annual_
Scientific_Meeting_NICE_Hypertension_Guidelines.html).
These, along with the NICE implementation materials (http://www.nice.org.uk/CG127), will help facilitate dissemination and implementation of this evidence based evolution of the NICE hypertension guidelines.

Could NICE guidance on the choice of blood pressure lowering drugs be simplified?

BMJ November 2011

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.

Among these, treatment would be dictated by cost or tolerability if all drugs were of similar
efficacy and safety and had an additive effect when used in combination. However, guidance from the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society emphasises differences between drug classes and combinations in blood pressure response and clinical outcomes.


NICE’s recommendations are based on the view that younger patients (≤55 years) are more responsive to drugs targeting the renin-angiotensin system than older patients; that β blockers are less effective than the other drug classes for the prevention
of stroke; and that
β blockers and diuretics lead to a clinically important increase in the risk of type 2 diabetes.

Consequently,its 2006 guidelines gave primacy to angiotensin modifying drugs and calcium channel blockers, with a substantial influence on prescribing behaviour in England and Wales (fig 1⇓).2 The updated guidelines published last August (www.nice.org.uk/ CG127) maintain this view, but how strong is the evidence?

Stratification by age

Current NICE recommendations represent an evolution of the view that blood pressure is best lowered with β blockers or ACE inhibitors in patients under 55 years (in whom an activated renin-angiotensin system may be an important mechanism) and diuretics or calcium channel blockers in older patients (because sodium retention, with suppression of the renin-angiotensin system, may be more important).

This was based primarily on the findings of a study (n=36) that rotated young patients through monthly treatment with each of four main classes of blood pressure lowering drugs and assessed the effect on blood pressure.

By 2006, NICE had relegated β blockers to third or fourth line therapy because of concerns about reduced protection from stroke, and last year NICE dropped diuretics as a first line option.
Renin declines with age, and the major drug classes do differ in their effect on the renin-angiotensin system. However, the performance of age as a proxy for stratifying blood pressure response or in comparison with measurement of renin concentrations (now possible with a rapid, cheap assay) has yet to be formally evaluated.

Moreover, a meta-analysis including data from 11 000 participants from 42 trials, which included
people younger than 55, concluded that the “blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects.” This conclusion even included combinations of two drugs that both suppress or activate renin.

Efficacy of β blockers

Two sources of evidence were influential in NICE’s relegation of β blockers from first line treatment: the Anglo Scandinavian Cardiovascular Outcomes Trial (ASCOT), published in 2005, and three meta-analyses examining the efficacy of β blockers in the prevention of cardiovascular events, published in 2005-6.9-11

ASCOT was a randomised trial comparing an amlodipine based treatment regimen (with addition of perindopril and then doxazosin if required) with an atenolol based treatment regimen
(with the addition of bendroflumethazide and then doxazosin if required) to achieve a blood pressure <140/90 mm Hg. The trial was terminated early on the advice of the data safety monitoring committee because of a significant treatment difference in favour of patients randomised to the amlodipine
based regimen for two secondary end points (stroke and total cardiovascular events).


There was no difference in the primary end point of non-fatal myocardial infarction or fatal coronary heart disease. Blood pressure was lower in the group randomised to amlodipine rather than atenolol by around 2.7/1.9 mm Hg.
The trialists’ analysis suggested the blood pressure difference was insufficient to explain the disparity in event rates, but an accompanying commentary reached the opposite conclusion.

A subsequent meta-analysis examined trials comparing β blockers with other blood pressure lowering drugs.9 Stroke risk was 16% higher (95% confidence interval 4% to 30%) among patients randomised to β blockers than among those taking other
drugs. Two other meta-analyses reached similar conclusions. However, the inclusion and exclusion criteria of these meta-analyses were not uniform.

A re-analysis shows that the pooled estimate of the comparative efficacy of β blockers for
preventing stroke is sensitive to which trials were considered eligible (see supplementary analysis on bmj.com). Furthermore, they did not account for blood pressure differences between the treatment arms.

The achieved blood pressure favoured the comparator drug over β blockers in all scenarios, which may bias the outcome in favour of the comparator drug. The blood pressure disparity is unlikely to be because β blockers are inherently less effective at lowering blood pressure than other drugs but rather because achieving a precisely equivalent blood pressure reduction in two arms of a comparator trial is extremely challenging. Nevertheless this is essential for a fair comparison of the efficacy of two drug classes.

Two new comprehensive meta-analyses now supersede these studies. These examined the efficacy of all major blood pressure drug classes (not just β blockers) in the context of the achieved reductions in blood pressure. The Blood Pressure Treatment Trialists Collaboration, which incorporated information from 190 606 participants across 31 treatment trials,concluded that all classes of drug were broadly equivalent with respect to protection from serious cardiovascular events.

The analysis indicated a log-linear association between blood pressure reduction and the relative risk of events, in keeping with predictions from observational studies. A second analysis by Law and colleagues, which included information from published trials among 464 000 participants, concluded the protective effect of lowering blood pressure on coronary heart disease was the same for all drug classes with two exceptions.
Calcium channel blockers had a small class specific advantage in protecting from stroke over all other classes.

The authors considered that this probably accounted for most of the apparent disadvantage of β blockers in stroke protection because calcium channel blockers had been the most common comparator drug
in trials of β blockers.
Law and colleagues also found β blockers to have a specific action over and above their blood pressure lowering effects in preventing a recurrence in the first few years after a coronary heart disease event.

Because blood pressure is an important risk factor for recurrent events in patients with established
cardiovascular disease, as well as those at risk of a first event,it had seemed counterintuitive that β blockers should be an unfavoured treatment before a patient has had a coronary event but a preferred option immediately afterwards. In the longer term, their benefits were consistent with the degree of blood pressure lowering and proportionally similar to that seen in individuals with no prior event.


Risk of type 2 diabetes
Patients receiving β blockers or thiazides rather than other drugs such as ACE inhibitors are at higher risk of diabetes. But what is the magnitude of the blood glucose increase; by how much is the risk of diabetes increased; and, importantly, how does this affect the risk of cardiovascular events? In the ASCOT trial, diabetes risk was increased among people randomised to the atenolol-bendroflumethiazide arm (hazard ratio for the comparison of groups randomised to amlodipine rather than atenolol was 0.70, 95% confidence interval 0.63 to 0.78), yet the average absolute difference in blood glucose concentration was only 0.2 mmol/L (SD 2.08 mmol/L, P<0.0001).

The seemingly substantial increase in the risk of diabetes arises because an average increase in glucose of as little as 0.2 mmol/L leads to a substantial increase in the proportion of people marginally exceeding the diagnostic fasting blood glucose threshold of 7 mmol/L and therefore being classified as diabetic (fig 3 on bmj.com).

However, the evidence is not compelling that this small average increase in glucose translates into a shortfall in protection from stroke or coronary heart disease. In the Asia Pacific Cohort Studies Collaboration (a participant level meta-analysis of 237468 people), a decrease in fasting glucose by 1 mmol/L was associated with a 21 % (18% to 24%) lower incidence of stroke and a 23% (19% to 27%) lower incidence of ischaemic heart disease.

If the association is causal, and assuming a log-linear relation between glucose and risk of cardiovascular events, an increase in fasting glucose of 0.2 mmol/L should confer about a 5% increase in the risk of stroke, which is less than the differences reported in the recent trials.

Moreover, recent overviews of prospective observational studies indicate that although the risk of coronary heart disease is linearly and modestly increased above a fasting glucose value of 5 mmol/L,the risk of stroke is substantially raised only at fasting glucose values well above 7 mmol/L (fig 4 in supplementary analysis on bmj.com).

Furthermore in the ALLHAT trial (in which 33 357 patients were randomised to chlortalidone, amlodipine, or lisinopril) there was a difference in blood glucose of 0.16 mmol/L in the amlodipinegroup compared with the chlortalidone group, with
an odds ratio for diabetes of 0.73 (0.58 to 0.91). Yet the hazard ratio for stroke was 0.93 (0.82 to 1.06). There was only a small blood pressure disparity between the chlortalidone arm and amlodipine arms (blood pressure difference amlodipine versus
chlortalidone 0.8 mm Hg systolic (P=0.03)/−0.8 mm Hg diastolic (P<0.001)).

This suggests that the observed differences in risk of stroke in these trials are more likely to be explained by differences between the treatment arms in blood pressure rather than glucose. The relevance of the small average increase in glucose is further questioned by recent trials that indicate that tight glucose control does not necessarily lead to a reduction in cardiovascular event rates.

Despite this, NICE cost effectiveness models were based on the assumption that β blockers provide less protection from stroke than all other drug classes (not just calcium channel blockers) and that any diagnosis of diabetes is associated with twice the risk of mortality and other cardiovascular disease events compared with no diabetes. It is not clear whether the known effects of β blockers in preventing recurrent coronary heart disease events were modelled in the economic analysis.

How does guidance compare internationally?

Guidance in the United States published before 2006
recommends diuretics as first line treatment, with β blockers given equal standing to the other drug classes.24 The European Society of Hypertension and the European Society of Cardiology guideline from 2007 also recommends β blockers and thiazide diuretics as first line options in the absence of contraindications, except among those with established metabolic syndrome or aparticularly high risk of diabetes.25 However guidance in Scotland and New Zealand has changed in line with NICE’s 2006 recommendations.


Resolving uncertainty
Network (mixed treatment) meta-analysis was used to evaluate the comparative efficacy and safety of the main blood pressure lowering drug classes in relation to cardiovascular events and
diabetes, but these analyses preceded the recent large influential trials and meta-analyses. An updated network meta-analysis that includes efficacy and safety outcomes and which accounts for blood pressure and glucose differences between treatment arms could help reduce any remaining uncertainty.

In the meantime, the most recent 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. This
simplification would benefit healthcare commissioners, doctors,and patients.