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Time to bury “hypertension”

Mark R Nelson
Med J Aust 2016; 205 (3): 103-104. || doi: 10.5694/mja15.01178
Published online: 1 August 2016

An absolute cardiovascular risk approach will better target patients who need pharmacotherapy

The publication of the Systolic Blood Pressure Intervention Trial (SPRINT), sponsored by the United States National Institutes of Health, has left physicians claiming that systolic blood pressure targets of < 120 mmHg are too low and unobtainable, and that the results are not generalisable to their “real” patients.1 Although it was ostensibly a “hypertension optimal treatment” trial, it was also, in effect, a quasi-trial of the treatment for elevated blood pressure in high risk individuals who would otherwise remain untreated. This can be argued because the study population were all high risk patients determined by age, clinical conditions or Framingham risk score, and the entry-level systolic blood pressure was 130 mmHg rather than the normal treatment threshold of 140 mmHg. The low entry level, with a mean systolic blood pressure of 139.7 mmHg, probably explains the low targets achieved in the intensive treatment group. The study demonstrated not only that the reduction of systolic blood pressure leads to benefits in decreasing the rates of all-cause mortality and cardiovascular morbidity and mortality, but also that this reduction could be achieved with relative safety, even for older patients, as there was no overall difference in serious adverse event rates between the intensive treatment group and the standard treatment group. This conclusion had also been arrived at in the Hypertension in the Very Elderly Trial, a randomised controlled study of blood pressure lowering in very old patients, where serious adverse events were actually lower in the treatment group compared with the placebo group.2 The accepted wisdom of “it only takes one broken hip to wipe out all that gain in cardiovascular risk” does not seem to hold true.3

The predictable criticism of the findings reflects the entrenched clinical concept of hypertension — that there is a magic figure above which you have the condition and below which you do not. SPRINT reinforces that lowering blood pressure to at least 120 mmHg may be beneficial for a high risk individual as no J-curve nadir was demonstrated. It is opportune to return elevated blood pressure to its continuous variable risk factor status rather than treat it as a dichotomous disease. After all, the very term “hypertension” is confusing to patients.4

Who should we treat with blood pressure-lowering drugs?

Initiation of pharmacotherapy should be reserved for those who will probably benefit in terms of preventing a major adverse cardiovascular event, and when this benefit clearly outweighs the potential harms of side effects and costs of treatment. Candidates are therefore those at moderate to high risk of such events in what is an asymptomatic condition. A simple algorithm populated by the most important determinants of cardiovascular disease risk is sufficient to identify the individuals who do not have a manifest disease. This is readily accessible with the Australian absolute cardiovascular risk calculator.5 Such an approach recognises that drug therapy should be considered in the context of the whole person, while acknowledging that action on risk stratification can be challenging and complex for many.

Implementing the absolute cardiovascular risk factor approach in Australian health care

Australian clinical practice has not yet widely adopted the absolute cardiovascular risk factor approach,6 despite the development of evidence-based guidelines by the National Vascular Diseases Prevention Alliance (NVDPA). These guidelines are the result of a collaboration of four peak bodies — Kidney Health Australia, the National Heart Foundation, the National Stroke Foundation and Diabetes Australia — and have the endorsement of the National Health and Medical Research Council (NHMRC).7,8 The NHMRC has also recently adopted the absolute cardiovascular risk approach as one of its priority cases for research translation.9

With such an approach, the recommended pharmacotherapy regimen will need to be changed for high risk “normotensive” patients and for low risk “hypertensive” patients. The first group comprises individuals who are at a high risk due to a clinical manifestation of cardiovascular disease or clustering of risk factors, but whose blood pressure has not crossed the 140/90 mmHg threshold. The National Prescribing Service, as part of its MedicineWise program, and the NVDPA have addressed this group through educational programs which use case vignettes of the unexpected fatal myocardial infarction of a late middle-aged male smoker who did not have hypertension or hypercholesterolaemia (http://www.nps.org.au/media-centre/media-releases/repository/latest-program-from-nps-medicinewise-targets-blood-pressure). SPRINT reinforces the benefits of treatment in this group.

The second group comprises those (often younger) patients with mildly elevated blood pressure, who are low risk but hypertensive and for whom drug treatment is not recommended. For this group, there is a concern that such individuals may be harmed due to a delay or absence of treatment, allowing irreversible pathological damage to occur, that is, to accrue adverse legacy effects. While research in this area is ongoing and has yet to demonstrate such effects, it does contrast with another clinical concern, that of overdiagnosis.10,11 Diagnosing an individual with a medical condition has adverse effects for those who have an asymptomatic condition where intermediate benefit is very unlikely; this also has opportunity costs to society because of the misdirection of limited resources. Such individuals do not remain untreated, just unmedicated, as attention is paid to adverse health behaviours, which, when addressed, have benefits beyond the cardiovascular system. In practice, such individuals are likely to delay rather than avoid drug therapy, as age is the most important determinant of risk; however, their years on therapy will be truncated without affecting their lifespan and quality of life. Evidence suggests that reassessment of risk is not required for most low to moderate risk individuals within 8–10 years of the diagnosis, with the exception of those close to treatment thresholds, for whom annual review is recommended.12

Given the limited uptake of the absolute risk approach to date, how can we encourage its increased use? One possible way is through the Pharmaceutical Benefits Scheme (PBS). The current PBS indication for blood pressure-lowering agents is hypertension, rather than a specified blood pressure threshold. Hence, prescribing would seem to be unimpeded by the absolute risk approach, given that such a definition is likely to be deferred to expert guidelines. Cholesterol-lowering agents, on the other hand, have a complex set of criteria for eligible prescribing on the scheme that are not solely based on a single serum cholesterol threshold (http://www.pbs.gov.au/info/healthpro/explanatory-notes/gs-lipid-lowering-drugs). To advance cardiovascular health care in Australia, the NHMRC Primary Health Care Steering Group recognised that uptake of the absolute risk approach could be enhanced by changing PBS criteria for statins from these criteria to one based more simply on an absolute risk threshold.9 To this end, the NHMRC is asking the Pharmaceutical Benefits Advisory Committee to consider aligning their prescribing conditions to the NHMRC-approved absolute cardiovascular disease risk guidelines.8 This would mean that all physicians would need to become familiar with the Australian cardiovascular risk calculator in order to access statins for their primary prevention patients. Once habituated, they may be more willing and able to apply it in the setting of treating elevated blood pressure.

With benefit demonstrated at lower thresholds and to lower targets, there is a greater imperative to move away from the hypertensive model of care as these thresholds and targets approach the ideal blood pressure of 115 mmHg,13 which would capture most of the population. Taking the absolute risk route will, on the other hand, target those who have a covert cardiovascular disease most likely to manifest clinically in the foreseeable future and, therefore, benefit from pharmacotherapy.


Provenance: Not commissioned; externally peer reviewed.

  • Mark R Nelson

  • University of Tasmania, Hobart, TAS

Correspondence: Mark.Nelson@utas.edu.au

Competing interests:

I am a member of an advisory committee for Amgen, a producer of a cholesterol-lowering agent, and a member of the Primary Health Care Steering Group of the NHMRC Research Translation Faculty.

  • 1. The SPRINT Research Group. A randomised trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103-2116.
  • 2. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887-1898.
  • 3. Howes F, Hansen E, Williams D, Nelson M. Barriers to diagnosing and managing hypertension — a qualitative study in Australian general practice. Aust Fam Physician 2010; 39: 511-516.
  • 4. Bokhour BG, Kressin NR. What is in a name? How biomedical language may derail patient understanding of hypertension. Circ Cardiovasc Qual Outcomes 2015; 8: 452-454.
  • 5. National Vascular Disease Prevention Alliance. Australian absolute cardiovascular disease calculator [website] www.cvdcheck.org.au (accessed Nov 2015).
  • 6. Bonner C, Jansen J, McKinn S, et al. General practitioners' use of different cardiovascular risk assessment strategies: a qualitative study. Med J Aust 2013; 199: 485-489. <MJA full text>
  • 7. Heeley EL, Peiris DP, Patel AA, et al. Cardiovascular risk perception and the evidence–practice gaps in Australian general practice (the AusHEART study). Med J Aust 2010; 192: 254-259. <MJA full text>
  • 8. National Vascular Disease Prevention Alliance. Guidelines for the management of absolute cardiovascular disease risk. Melbourne: National Stroke Foundation, 2012. http://www.cvdcheck.org.au/pdf/Absolute_CVD_Risk_Full_Guidelines.pdf (accessed May 2016).
  • 9. Trevena L, Nelson M, Harris M, Osborne R. Case for action proposal to NHMRC — The right care for the right person at the right time: improving the identification and management of absolute cardiovascular risk in the community. Submitted by the NHMRC Research Translation Faculty Primary Health Care Steering Group; Oct 2014. https://www.nhmrc.gov.au/_files_nhmrc/file/research/research_translation_faculty/rtf_cfa_primary_health_care_150518.pdf (accessed May 2016).
  • 10. Nelson MR, Chowdhury EK, Doust J, et al. Ten-year legacy effects of baseline blood pressure “treatment naivety” in the Second Australian National Blood Pressure study. J Hypertens 2015; 33: 2331-2337.
  • 11. Heath I. Overdiagnosis: when good intentions meet vested interests. BMJ 2013; 347: f6361.
  • 12. Bell KJ, Hayden A, Irwig L, et al. When to remeasure cardiovascular risk in untreated people at low and intermediate risk: observational study. BMJ 2013; 346: f1895.
  • 13. Freitag MH, Vasan RS. What is normal blood pressure? Curr Opin Nephrol Hypertens 2003; 13: 285-292.

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access_time 06:57, 20 August 2016
Leonard F Arnolda

We have concerns with the Perspective article by Mark Nelson [MJA doi: 10.5694/mja15.01178], particularly recommendations arising from SPRINT (1). A key point Nelson fails to mention is that the method used to measure blood pressure in SPRINT produces readings that are considerably lower than conventional office blood pressure by up to 11-16 mm Hg systolic and 3-12 mm Hg diastolic (2). Such differences limit direct applicability of SPRINT to current Australian practice. Additionally, as greater than 90% of participants in SPRINT were receiving antihypertensives prior to entry, it was not as Nelson states a ‘quasi-trial of high risk individuals who would otherwise remain untreated’.

Greater consideration is required regarding serious adverse events than portrayed by Nelson. In SPRINT 4.7% of participants in the intensive-treatment group and 2.5% in the standard-treatment group had serious adverse events that were classified as possibly or definitely related to intervention (hazard ratio, 1.88; p<0.0001). These serious adverse events were predominantly those usually associated with excessive blood pressure reduction such as hypotension, syncope, falls, and acute kidney injury or failure, which thoughtful clinicians take care to avoid. HYVET (mentioned by Nelson) is not an appropriate comparison to SPRINT as the target blood pressure of <150/80 was considerably higher and most adverse events were not considered treatment-related (3).

We agree with Nelson that the ‘absolute cardiovascular risk approach’ is appropriate in consideration of modifiable cardiovascular risk factors, of which one is blood pressure. However, available risk calculators have limitations including a failure to consider the most important (although unmodifiable) risk factor, namely individual genetics, and also that they rate all cardiovascular events (e.g. myocardial infarction or stroke) equally. When using risk calculators, we suggest gaining insight into the weighting of the various risk factors in the individual case by inserting and deleting each risk factor in turn in the risk calculator. Such an approach provides guidance to management of the ‘high risk normotensive’ patient described by Nelson where cessation of cigarette smoking, adoption of a healthy lifestyle including reduction of alcohol intake, and prescribing a statin would be an appropriate initial approach. The gain from using antihypertensives in such an individual is uncertain and small at best. In addition, time is required for better characterisation of blood pressure, both within and outside the clinic, and also to observe its response to life style modification. The HOPE-3 study supports such an approach, as in ‘intermediate-risk persons without cardiovascular disease’ the use of antihypertensives was not associated with reduction of cardiovascular risk, whereas lipid lowering with a statin was (4). A similar approach could be considered in Nelson's ‘low risk hypertensive'.

Competing Interests: Professor Arnolda chairs the the National Blood Pressure and Vascular Disease Advisory Committee, an expert committee of the Heart Foundation and chairs the High Blood Pressure Working Group of the Cardiac Society of Australia and New Zealand. He has received speaker fees from Pfizer. Dr Gabb is a member of the National Blood Pressure and Vascular Disease Advisory Committee, an expert committee of the Heart Foundation and has received a speaker fees from Pfizer. Professor Wing was a Past Chair of the National Blood Pressure Advisory Committee of the Heart Foundation.

Prof Leonard F Arnolda
University of Wollongong, Wollongong, NSW

access_time 03:28, 24 August 2016
Mark Nelson

I thank Arnolda and colleagues for their considered response. SPRINT utilised an automated office blood pressure (BP) method which is more accurate than usual practice and quite capable of being done in Australian clinical practice as nearly 20,000 of the same machines were previously distributed by the High Blood Pressure Research Council of Australia (1-3). These devices have been validated to a 1-2mmHg systolic BP accuracy (4, 5). I chose my term ‘quasi-trial’ advisably as the Oxford English dictionary defines this as ‘resembling or simulating, but not really the same as, that properly so termed’. Arnolda et al are correct and with time some individuals may cross thresholds for treatment on a BP criterion but many would not and would remain untreated under that strategy despite their high absolute risk.
Monitoring for expected serious adverse events (SAEs) suggests a form of confirmation bias. It is the total SAEs in each arm balanced against the demonstrated benefits that tells you if a particular strategy should be favoured or not. I agree that all risk calculators have limitations but compared to clinical judgement and individual risk factor stratification they are undoubtedly superior (6). The absolute risk approach does not differ from the individual risk factor approach in having lifestyle advice as a first line intervention but does differ is that it recommends immediate co-prescribing of risk factor reducing drugs as for high risk individuals likely to manifest major cardiovascular events in the short to intermediate period. Arnolda et al are correct that in HOPE-3 lipid lowering was statistically significant and BP was not (7). This can be explained by the modest BP reductions attained and that this study was a factorial study based on individual risk factors in intermediate, not high, risk individuals. If you do a Numbers Needed to Treat you would see that the combination of BP and lipid lowering medication was the most successful strategy.
(1) The SPRINT Research Group. A randomised trial of intensive versus standard blood-pressure control. NEJM 2015; 373: 2103-2116.
(2) Myers MG, et al. Automated office blood pressure measurement for routine clinical practice. MJA 2012; 197 (7): 372-373.
(3) Nelson MR, et al. Cluster-randomized controlled trial of oscillometric vs manual sphygmomanometer for blood pressure management in primary care (CRAB). Am J Hypertens 2009; 22: 598-603.
(4) Assaad MA, et al. Validation of the Omron HEM-907 device for blood pressure measurement. Devices and Technology 2002; 7: 237-241.
(5) White WB, Anwar YA. Evaluation of the overall efficacy of the Omron office digital blood pressure HEM-907 monitor in adults. Devices and Technology 2001; 6: 107-10.
(6) Peeters A, et al. Coronary heart disease risk prediction by Victorian General Practitioners. MJA 2004;180(5):252.
(7) Lon EM, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. NEJM 2016; 374: 2009-2020.

Competing Interests: No relevant disclosures

Prof Mark Nelson
University of Tasmania

access_time 05:36, 30 August 2016
Lindon Michael Harper Wing

We take issue the responses by Nelson. We acknowledge that many Australian GP’s possess the OMRON 907 as a blood pressure (BP) measurement device but currently there is no evidence that they use it in the automated manner specified in SPRINT (1). Nelson has missed the point that 90% of participants in SPRINT were receiving antihypertensives at entry into the study and therefore his statement that ‘many would remain untreated’ is incorrect.
We disagree with Nelson that ‘monitoring for expected serious adverse events (SAEs) suggests a form of confirmation bias’. In SPRINT methods to assess for adverse events were the same in both treatment groups, suggesting a significant role for confirmation bias is unlikely. The commonest SAE’s which were those usually associated with excessive BP reduction were significantly more frequent in the intensively treated group.
We disagree with Nelson concerning the approach to an individual with ‘high cardiovascular risk’ but a BP < 140/90. The risk calculator demonstrates that most gain (30-50% reduction in risk) in such an individual would come from smoking cessation and cholesterol lowering with a statin, the latter reinforced by the HOPE-3 results (2). The gain from BP lowering would be small (about 10%) and may be achieved by the associated life style modification. Extrapolation of the SPRINT results to conventional BP measurement in Australian practice suggests that an appropriate target systolic BP would be <130 mm Hg and not <120 mm Hg as in SPRINT.

REFERENCES

1. SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103-16.
2. Yusuf S, Lonn, E, Pais, P, et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2032-43.


Competing Interests: No relevant disclosures

Prof Lindon Michael Harper Wing
Flinders University

access_time 12:18, 2 September 2016
Mark Nelson

Thank you Wing et al for your further comments. AOBP is actively being promoted in Australian general practice though not monitored to my knowledge (1). I concede that that ‘some’ rather than ‘many’ would be a better word selection. I stand by my comments regarding confirmation bias. It is expected that adverse effects known to be associated with a strategy will be more prevalent in that arm of the trial. The overall serious adverse event (SAE) rate was 1793 (38.3) in the intensive arm and 1736 (37.1) in the standard arm (HR 1.04, P=0.25) meaning there was no more overall harm in the intensive treatment group. HYVET is illustrative not because of its treatment goal but because the elderly often remain untreated for fear of adverse events associated with therapy, where it showed overall lower SAEs (2). I agree that in a high risk individual all factors should be addressed including smoking cessation and cholesterol lowering. The residual mooted benefit of 10% from blood pressure lowering reinforces that therapy should only be instigated in such high risk individuals. Remember the alternate threshold for treatment regimen holds there is profound difference between the clinically insignificant and within measurement error 1 mmHg of SBP 139 and 140 mmHg.
(1) Myers MG, Nelson MR, Head GA. Automated Office Blood Pressure Measurement for Routine Clinical Practice. Med J Aust 2012; 197 (7): 372-373.
(2) Beckett NS, et al. Treatment of Hypertension in Patients 80 Years of Age or Older. NEJM 2008;358(18): 1887-1898.

Competing Interests: No relevant disclosures

Prof Mark Nelson
University of Tasmania

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