Comfort with Harm

Dong X, Ling Q, Zhao X, Song Q, Cai J. Benefit and Harm of Intensive Blood Pressure Control by Cardiovascular Risk. Hypertension. 2025 Aug;82(8):1392-1400. doi: 10.1161/HYPERTENSIONAHA.125.25162. Epub 2025 Jun 26. PMID: 40567237.

We all know the principle of Primum non Nocere — First, Do No Harm. To be clear, I hate hearing doctors in op-eds and social media posts pontificate about “our oath to do no harm,” because they either don’t know or don’t care that none of us actually swore to that, as it is not part of the Hippocratic Oath (https://www.health.harvard.edu/blog/first-do-no-harm-201510138421). Moreover, it is a nearly useless principle when caring for the sick, as was nicely laid out in this 2024 JAMA Pediatrics piece (https://jamanetwork.com/journals/jamapediatrics/fullarticle/2819056).

That said, in routine hypertension management, patients are not sick. Thus, there should be a high bar for avoiding harm. Titrating a medication up to the point that patients begin falling over, fracturing their hips, and sustaining head injury — not to mention kidney failure and high risk electrolyte abnormalities — for a very likely confounded sense of benefit is a tall order.

Let’s take a look at how hypertension researchers talk about harm by focusing on a recent study in the journal Hypertension entitled: “Benefit and Harm of Intensive Blood Pressure Control by Cardiovascular Risk.”

In this post hoc analysis of the STEP trial, the authors showed that in the overall population, intensive treatment is associated with a lower risk of cardiovascular events (HR, 0.76 [95% CI, 0.61–0.94]; P=0.011). Again, association is not causation, and even though this was a randomized trial, essentially all blood pressure studies are confounded by pleiotropic effects of the drugs that may vary by dose. However, when stratified by cardiovascular risk, the benefit was only significant in the highest tertile, although the authors misleadingly state that “The rate of the primary outcome in each 10-year CVD risk tertile was lower in the intensive group.”*

In terms of harm, intensive blood pressure control was shown to be more harmful than standard control in the highest two tertiles, with treatment related adverse events falling in the range of 6-9%. Even if benefit statistically outweighs harm, the chasm is not as impressive as we would want it to be.

For a profession that claims to live by the mantra of “Do no harm,” with all its complexities notwithstanding, our comfort with doing real harm for an uncertain benefit is concerning. This is not cancer treatment where we weigh objective remission against rates of neutropenia, or an antibiotic trial where rates of blood culture clearance are weighed against rates of acute kidney injury. What we are doing here is knowingly predisposing nearly 10% of initially asymptomatic people to a range of real harms based on claims of a statistical benefit that may very well be misleading (see tertiles 1 and 2). Since the goal is avoidance, the benefit is almost entirely theoretical, while the potentially fatal hip fracture is not. In this setting, “significantly greater benefit over the harm” is not enough.

In fact, the authors realize this, and “recommend caution,” but can we really predict with any degree of accuracy who is going to fall and break their hip, and almost as importantly, do so without bias (you can imagine the race and gender bias that would likely come into play)?

That said, does this mean forgo treatment with these ACEs, ARBs, and diuretics? No. But instead of chasing “intensive” blood pressure goals (or any other blood pressure goal for that matter), we should titrate to the maximum safely tolerated dose as we would with any other medication to minimize risk to the patient.

*This misleading statement was parroted by NEJM Journal Watch (https://www.jwatch.org/na58968/2025/07/18/intensive-blood-pressure-control-do-benefits-and-harms), which then stated, “Patients with the highest baseline risk gained the greatest benefit from intensive BP control.” In this study, only patients in the highest group were shown to have any benefit.