I happened to be in the car, with Radio 4 tuned in, last Wednesday (3rd Feb 2016) at 3.30pm. Dr. Mark Porter\u2019s programme, Inside Health<\/em> <\/a>(the transcript is below the recording), had just started and I heard a researcher saying that his trial had been stopped just over three years into a five year study because the benefit was already so dramatic. This is the holy grail of randomised controlled trials \u2013 \u2018we just had to stop the trial because it was unethical not to treat the control group because the intervention group was doing so well\u2019. Having seen this happen more than once, it can also happen, funnily enough, when gaps that had emerged between the two groups start to narrow…<\/p>\n The researcher being interviewed was Dr. Paul Whelton. Whelton is the chair of the SPRINT (S<\/strong>ystolic blood PR<\/strong>essure IN<\/strong>tervention T<\/strong>rial) steering committee. The full paper for the trial can be seen here<\/a>. (In Figure 3, the data available at four year shows the intervention and control group lines closer together than at the time the trial was stopped; funnily enough).<\/p>\n The trial enrolled over 9,000 people in the US between the dates of November 2010 and March 2013. There were many inclusion and exclusion criteria. These are very important, because they define the profile of people to which the results can apply. All participants had to be over the age of 50. And they had to have systolic blood pressure (the first number of the two e.g. the 140 in 140\/90) between 130 and 180. And they had to have had a significant risk factor for cardiovascular disease (already had cardiovascular disease, already got chronic kidney disease and\/or had a 10 year risk of 15% of higher on the Framingham scale). Two exclusion criteria were listed \u2013 the participant must NOT have diabetes and they must NOT have already had a stroke.<\/p>\n The aim of the trial was quite interesting \u2013 it was not<\/em> to see if blood pressure medications were better than not taking medications. It was to see if what they called \u201cintensive\u201d blood pressure (BP) lowering treatment (to medicate people to get them below 120 systolic BP) was better than \u201cstandard\u201d BP lowering treatment (to medicate people to get them below 140 systolic BP). The goal of this trial, therefore, was to see if giving more meds was better than giving fewer. The idea of not giving meds at all was not part of this trial.<\/p>\n The trial participants were also interesting \u2013 older people and sicker people \u2013 designed to ensure that there would be a decent number of deaths in a short period of time. This is not underhand \u2013 if the trial outcome is deaths, you need people to die!<\/p>\n 4,678 were analysed for the intensive treatment group; 4,683 were analysed for the standard treatment group. At the time the trial was stopped, 155 people in the intensive treatment group had died and 210 people in the standard treatment group had died. Table 2 in the full paper has the statistics on this. This was presented as a Hazard (risk) Ratio of 0.73, which can be presented as a 27% difference between the two interventions. Indeed, Whelton presented this on Inside Health<\/em> as \u201cIn fact their total mortality was reduced by close to 30% and I\u2019ve never been in a trial where we\u2019ve seen that before.\u201d<\/p>\n Relative risk<\/strong><\/p>\n That\u2019s relative risk, which I have frequently explained as highly misleading. The absolute risk of dying in any 1 year of the study was approximately 1 in 100. In the intensive treatment group 1.03 people in 100 died; in the standard treatment group 1.37 people in 100 died. That\u2019s 10 people in 1,000 vs. fewer than 14 people in 1,000. That\u2019s hardly \u201cStop the trial! People are dropping like flies!\u201d<\/p>\n Who didn\u2019t benefit<\/strong><\/p>\n Then is when it gets even more fun. Figure 4 in the paper<\/a> is called a forest plot or a blobbogram. I kind of like the second name. All you need to look for in a blobbogram is whether each horizontal line touches or crosses the vertical line, which is drawn at 1.0. Any horizontal line that touches or crosses that vertical line is NOT significant. It could have happened by chance. You should ignore it.<\/p>\n The blobbogram in this paper tells us that, the intensive treatment made a significant difference for:<\/p>\n – all participants grouped together; The intensive treatment made NO<\/strong> significant difference for:<\/p>\n – people who did have previous chronic kidney disease; For the majority of people, therefore, there was no benefit from intensive treatment. (As an aside, is it surprising that lowering BP to below 140 makes no difference to people whose starting BP is already below 132?!)<\/p>\n Thanks to Dr. Margaret McCartney on Inside Health<\/em>, the programme discussed the numbers needed to treat to impact one person. In McCartney\u2019s words: \u201cyou had to treat 90 people in order to delay one death over the three year period of the trial.\u00a0 Now that is important but it means that 89 out of those 90 people did not get benefit from having their death delayed and were at risk of just getting the side effects from the intervention.\u00a0Is that worth it or is it not?\u00a0 That\u2019s for the patient to decide, not for me.\u201d<\/p>\n Which brings us nicely on to…<\/p>\n The down sides<\/strong><\/p>\n The side effects were serious. A Serious Adverse Event is defined as a \u201cFatal or life threatening event, resulting in significant or persistent disability, requiring or prolonging hospitalization, or judged important medical event.\u201d<\/p>\n The paper reported: \u201cSerious adverse events of hypotension, syncope [fainting], electrolyte abnormalities, and acute kidney injury or acute renal failure… occurred more frequently in the intensive-treatment group than in the standard-treatment group.\u201d \u201cA total of 220 participants in the intensive-treatment group (4.7%) and 118 participants in the standard-treatment group (2.5%) had serious adverse events that were classified as possibly or definitely related to the intervention (hazard ratio, 1.88; P<0.001).\u201d<\/p>\n If you want to report deaths rates as 30% better than the standard treatment group, you should also report side effects as double that of the standard treatment group. Presenting benefit as 30% (relative) and the side effects as 4.7% (absolute) is naughty at best and deliberately misleading at worst. Some of those side effects are serious and nasty as well \u2013 acute kidney injury or acute renal failure? What would happen if the trial were kept to five years long, or extended for longer? Would significant numbers of people in the intensive treatment group die of kidney failure? How many will end up on lifelong dialysis as a result of this trial?<\/p>\n The honest patient conversation<\/strong><\/p>\n This kind of trial informs medical policy \u2013 it is intended to. That\u2019s why drug companies spend so much money funding research, researchers and research institutions. The messages that are best left in the minds of the medical world are 1) the trial stopped early i.e. you must get your patients on this treatment asap or you will be unethical and 2) there was a 30% difference in mortality i.e. you must get your patients on this treatment asap or you will be unethical.<\/p>\n Then the doctor conversation can be: \u201cI\u2019d like you to take this pill. It will reduce your risk of dying by 30%.\u201d<\/p>\n As McCartney suggested, the good doctor sets out the facts in an understandable way and lets the patient decide if absolute benefit is worth the known (side effect) risk. The honest doctor conversation in this case \u2013 only even to be considered with patients over the age of 50 \u2013 would be:<\/p>\n \u201cIf you are male, or over the age of 75, or have no previous chronic kidney disease, or are not<\/em> black, or have no previous cardiovascular disease, or have current systolic blood pressure under 132, AND over the age of 50 (because we didn\u2019t test younger people), AND don\u2019t have diabetes (because we didn\u2019t test for people with that), AND haven\u2019t had a stroke (because we didn\u2019t test for people with that) … if you then take 3 pills a day (that was the actual number of pills administered) every day for 3.26 years, you have a 1 in somewhere up to 90 chance (Note 1) of delaying death i.e. you might not die within the 3.26 years \u2013 you might die the day after, or sometime after, we don\u2019t know. Oh, and by the way, you double your (relative) risk of some serious side effects including acute kidney failure and you might faint here and there, so don\u2019t idle at the top of staircases.\u201d<\/p>\n Now who would jump at the meds?!<\/p>\n
\n– people who didn\u2019t have previous chronic kidney disease;
\n– people 75 years old or older;
\n– men;
\n– non black people;
\n– people who didn\u2019t have previous cardiovascular disease; and
\n– people whose starting blood pressure was under, or equal to, 132.<\/p>\n
\n– people under 75 years old (that\u2019s 82% of participants for starters);
\n– women;
\n– black people;
\n– people who did have previous cardiovascular disease;
\n– people whose starting blood pressure was greater than 132 (that was 66% of people).<\/p>\n
![](\"http:\/\/zoeharcombe.co.uk\/2018\/assets\/GuestSignupZHend.png\")
<\/a><\/p>\n