Blood pressure is one of the least understood and yet most intervened on metrics in modern medicine. Though we have found meager success in controlling blood pressure over the long-term (1,2) our attempts to translate these benefits to the acute setting of the emergency room have not been met with improved short-term outcomes. Traditionally acutely elevated blood pressure in the emergency room has been categorized into hypertensive urgency and hypertensive emergency. Thankfully this year ACEP published clinical guidelines on the treatment of asymptomatic hypertension stating that without any evidence of end-organ damage it is not necessary to treat hypertension acutely (11). And although it is no longer recommended to treat elevated blood pressure for purely the numbers sake, the vague nature of “end-organ damage” lends a great deal of uncertainty to this treatment dilemma. The inherent assumption that is being made is that the elevated blood pressure is the cause of the presenting symptoms, rather than a sign of the distress currently experienced by the individual or in many cases simply an incidental finding. With the recent publication of two trials addressing the very question of whether acute aggressive control of blood pressure is beneficial in either ischemic stroke or intracerebral hemorrhage (two of the more common hypertensive emergencies), our concepts of acute blood pressure management should be called into question.
In June of 2013, the NEJM published the initial findings from the long-awaited sequel to INTERACT, INTERACT-2 (3). In a trial examining if rapid reduction in blood pressure in patients experiencing intracranial hemorrhages led to improved neurological outcomes we hoped for greater clarity to aid our decision making. Though this trial was essentially a negative study, the authors’ statistical wizardry provided us with more uncertainty than assurances.
In a trial of 2,839 subjects, using the mRS in the traditional dichotomous fashion, the authors found statistical equivalence between patients treated with rapid blood pressure reduction, deemed the “aggressive therapy group”, and those in the standard therapy group. They claimed success in two of their novel secondary endpoints. The first of these was the infamous ordinal analysis of the mRS scale, most notable for its face-saving capabilities in the otherwise negative IST-3 (4). The second was the European Quality of Life Scale- 5 Dimension (EQ-5D), which the authors hoped would help them gain a broader grasp on patients’ functional capability.
The ordinal analysis performed by the authors found a statistical benefit to aggressive reduction in blood pressure with an odds ratio of 0.87. This was barely statistically significant with a confidence interval ranging from 0.77 to 1.00. Tucked away in the supplementary appendix are the results of a secondary adjustment performed on this ordinal analysis. This is the very same statistical correction used in IST-3 to show statistical significance in otherwise negative 6-month outcomes(4). Only on this occasion it did just the opposite. After correcting for baseline imbalances, the statistical significance of their ordinal analysis vanished. In what I can only imagine was an attempt to hide findings that would weaken their already tenuous outcomes they surreptitiously published these results in what is the scientific journal equivalent of the classifieds. Next the authors claimed the difference of 0.05 on the EQ-5D scale was proof of significant improvement in functional outcome. They failed to mention that though this difference reached statistical significance, it was below the 0.074 threshold commonly regarded to be the lowest meaningful difference on this 100 point scale (5).
In November 2013, He et al published the CATIS trial in JAMA, which examined whether rapid reduction in blood pressure was beneficial to INTERACT-2's counterpart, the ischemic stroke (6). The authors randomized 4,071 patients to rapid blood pressure reduction (using a variety of agents) of 10-25% within the first 24 hours or no management of blood pressure. Mortality and functional neurologic outcomes were measured at 14 days and 3 months. Like INTERACT-2, in the CATIS trial neurological function was assessed in person by a trained neurologist and research nurse blind to the treatment assignment. This form of data collection surely led to far more robust and reliable measurements, as compared to earlier trials such as IST-3, which measured its long-term outcomes by mail-in survey (10).
In terms of feasibility, the intensive therapy group was reasonably successful. As early as 4 hours there was a “significant” difference in the mean blood pressures between the groups. A difference that remained consistent as far out as 3 months. This unfortunately was as far as their success reached. Despite these achievements in blood pressure control, no significant differences were found in any of the multitude of endpoints examined. Mortality and neurological endpoints were almost identical at both 14 days and 3 months. Even the ordinal analysis the authors performed and included as a secondary outcome, (which in both IST-3 and INTERACT-2 found subtle shifts in neurological outcomes that went undetected by the more traditional dichotomous measure), was unable to detect a difference between the two groups.
This statistical equivalence cannot even be viewed as a minor victory, claiming at the very least safety in acute blood pressure management. Given the open design of the trial without a placebo control, the intensive therapy group had significantly more time and effort invested in their care. Based on this inherent bias one would expect the intensive group to have performed better. There may in fact be a hidden harm of aggressive blood pressure management that is veiled in Hawthorne’s shadow.
There are many examples in the recent medical literature of us being led astray in our attempts to impose normal physiologic parameters in situations that are entirely physiologically abnormal. The NICE-SUGAR trial demonstrates that tight control blood glucose levels in critically ill patients leads to worse outcomes than a more lenient approach (7). The TRICC and ARDSNET trials illuminated the same concepts for normalizing hemoglobin and PCO2 levels (8,9). So too, CATIS and INTERACT-2 should influence how we think of blood pressure in the acute setting. Instead of the unhelpfully vague classification of hypertension with “end-organ-damage” as an emergency necessitating treatment, we should take a more disease specific approach. What is the cause of the elevation in blood pressure and does that specific condition benefit from the acute manipulation of this hypertensive state? The list of hypertensive emergencies that have been shown to benefit from rapid blood pressure management have become diminishingly small. Currently, of the pathologies listed as “hypertensive emergencies”, only aortic dissection, acute pulmonary edema and preeclampsia have demonstrated benefit from a reduction in blood pressure in the acute setting. Otherwise elevated blood pressure should be viewed as sign of distress rather than a cause, and our futile pursuit of normality in an anything but normal state may in fact interfere with the patient's natural compensatory response to the event in question.
1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
2. Benavente OR, Coffey CS, Conwit R, et al; SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial [published correction appears in Lancet. 2013;382(9891):506]. The Lancet. 2013;382(9891):507-515.
3. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-65.
4. The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. The Lancet May 23, 2012
5. Stephen J. Walters and John E. Brazier. Comparison of the Minimally Important Difference for Two Health State Utility Measures: EQ-5D and SF-6D Quality of Life Research Vol. 14, No. 6 (Aug., 2005), pp. 1523-1532
6. He et al. Effects of Immediate Blood Pressure Reduction on Death and Major Disability in Patients With Acute Ischemic Stroke. The CATIS Randomized Clinical Trial. JAMA Published online November 17, 2013.
7. The NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med 2009; 360:1283-1297March 26, 2009
8. HÉBERT et al. A Multicenter, Randomized, Controlled Clinical Trial Of Transfusion Requirements In Critical Care. N Engl J Med Volume 340 Number 6 Feb 11, 1999
9. The Acute Respiratory Distress Syndrome Network. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med 2000; 342:1301-1308 May 4, 2000.
10. Dennis et al. Determining the modified Rankin score after stroke by postal and telephone questionnaires. Stroke 2012; 43: 851–53.
11. Wolf et al. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients in the Emergency Department With Asymptomatic Elevated Blood Pressure. Annals of Emergency Medicine. Volume 62 No 1 : July 2013