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• Author's response
  Kit Byatt
  Published on: 19 May 2014
• Overreacting to possible over-treatment? Hypertension treatment in the very elderly.
  Ken Uchino
  Published on: 10 March 2014

• Published on: 19 May 2014

  Author's response

  • Kit Byatt, consultant general physician & geriatrician

  Dear Editor,

  I am very grateful to Ken Uchino for amplifying and clarifying the detail of some of the points I was trying to make within the word limits of a 'Perspectives' paper. I suggest there are four key elements:

  1. The epidemiology is indeed complex and I am neither an academic nor an epidemiologist. However, it would appear that we can agree that there is indeed a difference between 'younger old'...

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  Dear Editor,

  I am very grateful to Ken Uchino for amplifying and clarifying the detail of some of the points I was trying to make within the word limits of a 'Perspectives' paper. I suggest there are four key elements:

  1. The epidemiology is indeed complex and I am neither an academic nor an epidemiologist. However, it would appear that we can agree that there is indeed a difference between 'younger old' (i.e. 65-75) and 'older old' (i.e. 80+), both in relative and absolute risk - albeit in opposite directions. The key point here is not the strength of the associations with age, but the magnitude of impact of treating the risk factor at any given age. This is where interventional trials come in.

  2. As I pointed out in my paper, the data about treating hypertension in 80+ year olds accumulated prior to HYVET were very suggestive of benefit; they predicted HYVET would give a definitive answer. HYVET - by far the largest trial looking at patients aged 80+ - failed to live up to this promise. Sadly, the premature termination of the trial (because of excess mortality in the placebo group) arguably raised more questions about the clinical applicability of its results, than the trial answered.

  3. The PROSPER trial examined the use of statins in European patients initially aged 70-82 (mean 75), and followed up for an average of 3.2 years. Nearly 20% of patients entered into the 4-week single-blind placebo lead-in period failed to proceed to the randomised period (either for using <75% or more than 120% of placebo, or because they refused to participate). This raises questions as to generalisability. Whilst reducing cardiovascular events, the intervention failed to show a reduction in stroke. I fully accept that absence of evidence is not necessarily evidence of absence, but this must surely raise questions as to the magnitude of any true effect.

  4. None of these trials looked into the patients' preferences and priorities re outcomes. I argue that these change significantly with advancing frailty and incapacity (which in turn increase disproportionately with, but are not confined to, increasing age).

  If we cannot even be certain of the ostensibly simple quantitative aspect of the decision (the certainty of the magnitude of the treatment effects), how can we properly weigh that up against the much more difficult to define qualitative aspects (the beliefs, values, and priorities of my patient)?

  My central point is that without robust evidence applicable to the patient in front of me - usually over 80, and often very frail - how can I help the patient to reach truly informed consent? I may well have some of the estimates of magnitude wrong, but the principle still stands. A treatment decision is only as strong as its weakest link. I suggest that there are so many weak links in this particular evidence chain that it is almost impossible to reach a decision that all doctors would support. Suggesting that a simple 'one size fits all' (i.e. algorithmic guideline- based) solution would be appropriate is simplistic. Without more data we cannot be sure.

  For all these reasons I strongly urge that we undertake randomised trials of withdrawals of treatment in real life elderly patients (both frail and robust). This has the potential to find out how much impact these interventions have in clinical practice, as opposed to in the rarefied environment of scientific clinical trials.

  In the UK NHS we arguably should have a real opportunity to use 'big data' in real life in this way to find out if there are any signals there amongst the noise. A simple pragmatic trial involving tens of thousands of people would surely have a good chance of giving us the information we need? If the NHS funded this with the money currently earmarked for hitting treatment targets in those over 80, it would not take long to answer this question.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 10 March 2014

  Overreacting to possible over-treatment? Hypertension treatment in the very elderly.

  • Ken Uchino, Associate Professor of Medicine (Neurology)

  Dear Editor,

  While I agree with Dr Byatt that it is important to discuss with patients the choices of treating risk factors to prevent disease, the basis for the discussion needs to be clarified and fine-tuned.

  Epidemiology: The attributable risk of hypertension in stroke decreases in the elderly. This phenomenon may be partly because other factors such as atrial fibrillation become more dominant factor....

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  Dear Editor,

  While I agree with Dr Byatt that it is important to discuss with patients the choices of treating risk factors to prevent disease, the basis for the discussion needs to be clarified and fine-tuned.

  Epidemiology: The attributable risk of hypertension in stroke decreases in the elderly. This phenomenon may be partly because other factors such as atrial fibrillation become more dominant factor. Framingham Study quoted in the paper is only one study. Pooling data from multiple studies, Prospective Studies Collaboration has reported that that higher risk of stroke mortality is observed with higher systolic and diastolic blood pressures across blood pressure ranges into age 80s.[1] The relative risk conferred with higher blood pressure diminish with age, but still in age 80s, 20 mm Hg increase in systolic blood pressure (SBP) is associated with ~1.5 fold increase in stroke. That compares with ~2.8 fold increase in risk of stroke in age 40s. But the absolute risk difference with increase in SBP or DBP is greater in old age.

  Even if Dr Byatt's reading of epidemiologic data is correct, a lack of observed association disease (stroke) with a risk factor (hypertension) does not necessarily translate that intervening on the factor would not reduce disease. This was clearly shown in case of cholesterol, where no consistent association with stroke risk has been shown in multiple studies.[2] Yet, clinical trials using statin class of cholesterol lowering medications have shown that stroke is indeed reduced if the study size is large enough in both primary and secondary prevention settings.[3, 4] We cannot assume that because the contribution of hypertension is smaller as one gets older, that treatment would not reduce stroke.

  Trial data: There is a consistent finding from clinical trials of blood pressure reduction comparing different targets or regimens that SBP reduction of 10-20 mm Hg confer a relative reduction stroke by about 30- 40%. Most studies confirm that stroke is very sensitive to blood pressure.[5] The finding of the HYVET study mentioned consistent in relative risk reduction of fatal and nonfatal stroke by 30% (p=0.06) with SBP difference in 15 mm Hg between the groups. The study may have be underpowered to reach statistical significance.

  One needs to keep in mind that the risk of stroke is low in the relatively healthy elderly individuals in clinical trials that mostly consists of persons free of cardiovascular disease. HYVET study with 80 years of age or older and found a rate of stroke of 1.7% per year in the placebo group. Active treatment results in a number needed to treat of 94 over 2 years to prevent one stroke. For comparison, in ALLHAT, with the mean age of 67, the annual stroke rate was ~1% per year.[6]

  Primary prevention is a challenge because the event rate and absolute risk reduction by intervention is low, even if relative risk reduction is large. In the elderly, the risk of events is higher, but the time horizon is also shorter. The discussion should not necessarily focus on the absolute risk reduction and the number needed to treat, but put the context of the outlook of the elderly individuals into the next several years, some of whom are living into elderly age in relative good health. Prioritizing may be important. What are the important diseases to prevent, screen, treat? While Dr Byatt focuses on stroke, treatment of hypertension reduces strokes, congestive heart failure, and myocardial infarction. While I agree with the recent JNC 8 recommendation to question the same blood pressure target across ages, hypertension cannot be simply viewed as over treated.[7]

  References

  1) Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903-13.

  2) Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370(9602):1829-39.

  3) Taylor FC1, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA 2013;310(22):2451-2.

  4) Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8(5):453-63.

  5) Staessen JA1, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;358(9290):1305-15.

  6) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997

  7) James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311(5):507-20.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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