Blood Pressure
High blood pressure is probably the most prevalent disease in the western world. The WHO estimates that at least 20% of the world's adult population has high blood pressure (a.k.a. hypertension), which is usually defined as a systolic blood pressure over 140 mmHg and/or a diastolic blood pressure over 90 mmHg (the systolic pressure is the pressure in the arteries when the heart is contracting, while the diastolic pressure is the pressure when the heart is relaxing).

The reason high blood pressure is considered a bad thing is because it is harmful to lots of different organs. It damages the arteries, leading to heart attacks and strokes. It damages the heart muscle, leading to heart failure. It damages the kidneys, resulting in kidney failure.

A problem is that in 90% of cases, no specific cause can ever be identified. This is known as essential hypertension, which is a rather odd name, since there doesn't seem to be anything essential about it. Hypertension is non-existent among primitive hunter-gatherers, suggesting that there is something about our western lifestyle that causes it.

But rather than figuring out what in the diet and lifestyle is causing the high blood pressure, and doing something about that, most people would supposedly rather take a pill every day for the rest of their lives and be done with it. Which is why we have a bazillion different blood pressure lowering drugs, and why many people with "essential" hypertension are on two or three or even four of these drugs at the same time.

It might surprise you to learn that when blood pressure lowering drugs were first introduced to the market and prescribed to patients, there was little evidence that they actually helped the patients live longer. They were introduced solely based on the fact that they lowered the blood pressure, which was assumed to be a good thing. But here we have a bit of a problem, because if the body decides to increase the blood pressure, there is probably an underlying reason. That reason might be that certain organs don't think they're getting sufficient oxygen, and are therefore telling the circulatory system to work harder in order to increase the level of oxygen delivery.

And if some part of the body has determined that it needs a higher blood pressure in order to function properly, then dropping the blood pressure might not be a good idea. It might for example cause the kidneys to fail, or the brain to temporarily cut out, causing the person to faint, fall down, and break their hip or suffer an intracranial bleed. Which is why we need studies that show whether the benefits of these drugs outweigh their potential harms.

That is where a systematic review that was recently published in the British Medical Journal comes in. The review was funded by the Wellcome Trust, the Royal Society, the National Institute for Health Research, Cancer Research UK, and a Canadian research fund. It included all randomized trials of blood pressuring lowering medications that provided data on adverse events, and that had at least 650 patient years of follow-up (a cut-off that was set for reasons of practicality, in order to decrease the workload for the reviewers - very small studies generally take as much work to understand as large studies, even though the information they provide is much less useful).

58 randomized controlled trials were identified that fulfilled the criteria, with a total of 280,000 participants followed for a median of three years. Most were comparing a single blood pressure lowering drug with a placebo, while some compared more intensive treatment with less intensive treatment (a topic I've written about before).

So, what were the results?

Let's start with the good news. Anti-hypertensive treatment was associated with a 7% reduction in the relative risk of dying over the course of follow-up and a 16% reduction in the relative risk of stroke. These reductions were statistically significant. Unfortunately, there was no statistically significant reduction in the risk of having a heart attack.

Then the bad news. Anti-hypertensive treatment was associated with a 28% increase in the relative risk of fainting, that was statistically significant. There was, however, no statistically significant increase in the frequency of falls, which is quite strange, since fainting pretty much always implies falling. The only way I can make sense of this weirdness is that falls due to fainting and falls not due to fainting were separated in to two different categories, with falls due to fainting categorized as "fainting", and falls not due to fainting categorized as "falls". Since blood pressure lowering medications cause you to fall by causing you to faint, it makes sense that they would cause an increase in falls due to fainting but not in other types of falls.

Anti-hypertensive treatment was also associated with an 18% increase in the relative risk of acute kidney injury, an 89% increase in the relative risk of hyperkalemia (high potassium levels in the blood), and a 97% increase in the relative risk of hypotension (blood pressure that is too low). These were all statistically significant.

How clinically meaningful they are is harder to answer. "Acute kidney injury" could mean anything from a small temporary bump in creatinine (a blood marker used to measure kidney function) all the way to full blown kidney failure requiring dialysis. "Hyperkalemia" could mean everything from a slighly elevated potassium, which has no clinical relevance, to a dangerously high potassium that could at any point cause the heart to stop beating. And "hypotension" could mean anything from a slightly low blood pressure to circulatory collapse and impending death.

So the only one of these adverse events that we know is definitely meaningful to patients is the increase in fainting. The others could just be small aberrations in different parameters that don't have any noticeable effect on patients' quality of life. We don't know. However, the fact that people on the blood pressure medications were overall less likely to die than people on placebo is encouraging, suggesting that the hyperkalemia and acute kidney injury and hypotension are for the most part at the more benign end of the spectrum.

One problem with the systematic review is that the vast majority of studies were comparing a single blood pressure medication with placebo. Different blood pressure medications work in different ways. Some cause arteries to dilate. Some cause the body to hold on to less fluids. Some cause the heart to beat less powerfully. This is why it's possible to combine different blood pressure lowering drugs and achieve a larger reduction in blood pressure than you would with just one drug.

For the same reason, it's reasonable to assume that someone getting multiple blood pressure lowering drugs has a much bigger risk of fainting, to take one example, than someone taking just one drug. The more different types of anti-hypertensive drugs you're taking, the more of the body's different systems for maintaining sufficient blood flow to the brain and kidneys are being inhibited.

So a review that is looking almost entirely at studies that only give patients one blood pressure lowering drug might significantly underestimate the number of adverse events experienced in reality, where patients are often combining multiple drugs. This goes back to the problem of polypharmacy, that I've written about previously. The more different drugs a patient is taking, the harder it is to predict what's going to happen.

As I wrote about in my article comparing intensive blood pressure treatment to more moderate treatment (comparing a target of 120 systolic to a target of 140 systolic), people in the intensive treatment group had a 35% increased relative risk of fainting compared to people in the moderate treatment group and a 69% increased relative risk of acute kidney injury. Remember, this is on top of the increase in these events already seen in people in the moderate treatment group. It is very possible, in fact quite likely, that there is an inflection point, where adding additional blood pressure lowering drugs has a negative impact of longevity, even if the patient still technically has a high blood pressure.

The authors of the review do point out one thing that I think is very important. The studies included in the review have for the most part been carried out on relatively healthy people with high blood pressure. They haven't been carried out on the multi-morbid elderly who are often the heaviest users of these drugs in reality. The multi-morbid elderly have less ability to compensate for the changes to their physiology induced by blood pressure lowering drugs, and it is therefore likely that they suffer adverse events at a higher rate than was found in the review.

What can we conclude?

In general, people with high blood pressure who take a blood pressure lowering drug do appear to live a little bit longer than people who don't. They also faint more often and their kidneys don't function as well. It is unclear whether the benefit seen here extends to the multi-morbid elderly, who are more likely to experience adverse events like fainting and acute kidney injury, and also more likely to die from these adverse events when they happen.