How often can one clinical trial measuring important endpoints be 1) randomized and controlled 2) encompass large numbers evenly balance between two treatment arms 3) use state of the art monitoring technology 4) have no apparent financial conflict and 5) transform medical care immediately in millions of patients? Indeed, this is an unusual list to check off but it occurred in the last few weeks with the publication of the Hygia Chronotherapy Trial. This study has immediately transformed my preventive cardiology practice and might be relevant to your health too.
What Was the Question?
The Hygia Chronotherapy Trial was based on prior observations that some medications, including the commonly used ACE and ARB pathways inhibited by some of the most popular choices in practice (like lisinopril, ramipril, losartan and telmisartan) have peak activity at night and taking these medications at night may have more efficacy. Furthermore, prior studies using ambulatory blood pressure monitors ( or ABPM which is wearing a cuff on the arm for 24–48 hours with programmed measurements of blood pressure through the day and night) identified that a dip in blood pressure at night was the strongest predictor of benefitting from blood pressure medications. Therefore, the trial randomized patients on an existing blood pressure regimen of 1–3 medications to taking them all at night or all in the AM.
Who Were Tested and How?
The investigators used a network of primary care clinics in Spain and identified 19,084 participants. They were followed at least annually for just over 6 years. Annually they were seen and wore a 48 hour ABPM. The number of subjects who suffered a primary cardiovascular disease (CVD) event (cardiovascular death, heart attack, stroke, cardiac intervention like bypass surgery or stent, and congestive heart failure) were tabulated.
What Was Found?
As the investigators reported, During the 6.3-year median patient follow-up, 1752 participants experienced the primary outcome. Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio — adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event. The primary CVD outcome was reduced overall by 45% and each of its single components were also reduced (CVD death lowered by 56%, heart attack 34% lower, coronary revascularization 40% lower, heart failure 42% lower, and stroke 49% lower).
Why Was There So Much Benefit to PM Medications?
Prior studies had shown that the blood pressure while asleep was the most accurate at predicting future CVD events. In the Hygia Trial, daytime blood pressure was similar in both groups but sleep BP was lower in those taking all their medications at night. In ways not completely understood, normalized sleep BP, called normal dipping, has a profound impact on the health of the endothelium lining the 50,000 miles of arteries in the body
What Are the Implications?
For the majority of patients taking BP medications, a discussion with their healthcare practitioner about switching all medications to night time use is imperative. Some patients are taking medication dose at twice a day frequencies and if they remain on their program, no change would occur. However, many of these, such as those taking losartan twice a day, could ask to switch to a long acting similar agent like telmisartan, and take it at night only. Some challenging BP patients are taking medications spaced out 2–3 times a day and it may be unwise to quickly abandon this dosing if it is achieving control fo the BP. Some patients are taking a diuretic (water pill) and may be hesitant to take it at night although this was done in the Hygia Trial and compliance was very high.
For most patients, the goal of BP therapy is not symptom relief but the hope that future CVD events will be avoided. Adopting bedtime dosing for most patients may translate to literally millions of events avoided and should be adopted rapidly.