CME INDIA Presentation by Admin.

New study shows 45% reduction in CV events if antihypertensive drug prescribed at bed time vs. morning! – European Heart Journal (2020) (41, 4565–4576 CLINICAL RESEARCH doi:10.1093/eurheartj/ehz754) Hypertension clearly advocates to change our clinical practice.

Take home Message

• Routine ingestion by hypertensive patients of >_1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep time relative BP decline, i.e., BP dipping) and, most importantly, markedly diminished occurrence of major CVD events. (EHJ)

A brief journey of this study

• Multicentre, controlled, prospective endpoint trial,
• 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) assigned (1:1) to ingest the entire daily dose of >_1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532).
• During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke).
•  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—of the primary CVD outcome

[0.55 (95% CI 0.50–0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34–0.56)], myocardial infarction [0.66 (0.52–0.84)], coronary revascularization [0.60 (0.47–0.75)], heart failure [0.58 (0.49–0.70)], and stroke [0.51 (0.41–0.63)].

• Results establish, first, greater ABP control in patients of the bedtime treatment than in those of the awakening-treatment regimen.

CME INDIA Discussion

Dr Awadhesh K Singh, DM, Endo., Kolkata:

• Always prescribe antiHTN drug at bed time. I am tried to convince my physician colleague that there is lot difference in outcome. Find above paper 45% reduction in CV events when drug prescribed at bed time vs. morning! Please change your habit 🙏🏽🙏🏽

Dr Anil Motta, Sr Consultant Medicine, Max Hosp., Delhi:

• Thanks for reinforcing this! A bedtime drug regimen was also linked to a 44% drop in heart attack risk; a 40% drop in the risk for coronary revascularization; a 42% lower risk for heart failure; and a 49% dip in stroke risk.

Dr Ripun Borpuzari, Sr Internist, Jt director, Govt of Assam:

• I fully endorse and do follow it. At least one drug in the evening time. It does also reduce some side effects of some antihypertensives. 🙏🙏

Dr Noni G Singha, Sr Physician, Dibrugarh, Assam:

• Timing of antihypertensive dose is best decided after ABPM.
• People who are non-dippers at night or people with morning surge are best benefitted night time dosing of Anti HTN. Moreover, diabetic and CKD, Sleep apnoea people are better treated with night time anti HTN. Again, those who have day time or higher office BP people are better managed with morning dosing.
• Dosing also depends on type of antihypertensive used e.g., ARB is better at night as highest RAS activity is highest at night and pharmacokinetics is favourable at night dosing, Diuretic are more accepted in morning hours (best adding second Anti HTN at night with them).
• Also, some molecule like Enalapril, nifedipine retard etc do not cover 24 hrs so need twice dosing.
• If on multiple antihypertensive then at least one antihypertensive at bedtime is advisable.

Dr Awadhesh K Singh, DM, Endo., Kolkata:

• Your points are fair and well taken. Exceptional situation are always different issues altogether. Example- beta blockers won’t be preferable at bed time; diuretics might disturb sleep due to frequent urination etc etc!

Dr Ashok Kumar, DM Neuro, Ranchi:

• Don’t know what is the accepted practice today. But I usually give Diuretics and Beta-blockers in morning. Usually combine a night dose of other anti-HTN’s — ARB, CCB.

 Dr Venkatesh Molio, Maregoan, Goa:

• If you have a truly 24-hour acting drug – Can give anytime.
• If drug acts less than 24 hours give twice or preferably at bedtime.
• If two meds are used-At least one should be bedtime
• Diuretics preferred daytime
• Betablockers preferred daytime.

Dr Awadhesh K Singh, Kolkata:

• A big No! Even a drug supposedly having 24 hour action has tail or waning effect in the last 4 hour. And, therefore if you give it in morning it’s action will be negligible next early morning where all CV event peaks!!! Period

Dr Vijay Arora, Phy Max hosp., Delhi:

• Specially in nonDippers in case of anti-hypertensive medications

Dr Ananda Bagchi, Kolkata:

• HARMONY Trial has shown that in treated hypertensive pts with stable BP levels, the timing of antihypertensive drug administration did not affect mean 24 hrs ABPM levels or quality of life.
• Hence there are no good data to recommend nocturnal dosing of antihypertensive drugs.
• Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing.
• HARMONY trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing.
• Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am–10 pm) and nighttime (10 pm–7 am) blood pressure levels nor on clinic levels.
• Stratification by age (≤65/≥65 years) or sex did not affect results.
• In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels.
• This was the first randomized trial to evaluate and to show that taking usual blood pressure-lowering medications either all in the evening or in the morning did not impact on 24-hour ambulatory blood pressure levels or clinic blood pressure levels.
• Pending further definitive evidence (particularly the results of the TIME [Treatment in the Morning Versus Evening] trial) patients should take their antihypertensive medications at a time which option 

Dr N K Singh:

• Originally HARMONY published27 Aug 2018 https://doi.org/10.1161/HYPERTENSIONAHA.118.11101 Hypertension. 2018;72:870–873 and the EHJ article mentioned is latest
• I think, as per emerged consensus, we should follow bed time

Dr Anupama Ramkumar, Phys., Clinical Researcher, Ahmedabad:

• With drugs that have a once daily dose per the label- the patient achieves steady state within 5-6 half lives, therefore there is not a significant trough in drug concentrations.All the very reason to reinforce that the patient takes the drug regularly at around the same time each day.

Dr Ripun Borpuzari, Sr Internist, Jt director, Govt of Assam:

• The morning sympathetic charge is to be reduced, do we need to give the LA BB in the bed time rather than in the morning? I do not find any specific reason why BB should not be given in the night. Any data on better reduction of cv events when given in the morning?

Dr Basab Ghosh, Agartala:

• An evening dose of a beta-blocker is more effective than a morning dose in reversing adverse changes in the autonomic nervous system activity in CHF patients.
• If single pill antihypertensive, best time is at bedtime. If multiple pills, better one tablet in the morning for better 24 hour protection.

Dr Sunil Kota, Endocrinologist, Orisa:

• Do beta blockers at bed time convert non dippers into extreme dippers?

Dr Awadhesh K Singh, DM, Endo., Kolkata:

• Sleeping reduces HR and BB at bed time will further lower it. Isn’t it so simple? 😊🙄

Dr Narsingh Verma, Lucknow:

• We have a study in which  ACEI have been used to produce pharmacological dipping in Diabetic nondippers In this study even albuminuria was reduced after achieving dipping pattern

Dr Basab Ghosh Agartala:

• That’s one reason, the dictum is ACEI or ARB should be preferred at bedtime.

CME INDIA Learning Points

• Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects.
• Dedicated studies on the timing of administration of medicines are sparse, and more studies are required. As it stands, information provision to health professionals about the optimal “time” to take medications lags behind emerging evidence
• EHJ (2020) study gives very valuable input about the “best circadian time” to take anti hypertensive medications
• Multiple prospective clinical trials document improved normalization of asleep blood pressure (BP) and 24 h BP patterning—increase in sleep-time relative BP decline towards the more normal dipper profile—when conventionally formulated single and combination hypertension medications are ingested at bedtime than upon awakening
• Control of sleep-time BP by proper choice of hypertension treatment time is clinically relevant.
•  Findings of numerous independent prospective studies and meta-analyses demonstrate that the asleep BP mean determined by ambulatory BP (ABP) monitoring (ABPM) is a significantly more sensitive prognostic marker of cardiovascular disease (CVD) risk than either daytime office BP measurements (OBPM) or the ABPM-derived awake or 24 h BP mean.
• We can  conclude that the significant 45% reduction in CVD outcome achieved by ingestion of the entire daily dose of >_1 BP-lowering medications at bedtime, compared with ingestion of all such medications upon waking is partly linked to better achievement of those novel therapeutic goals through improved targeting of underlying circadian rhythm-organized biological mechanisms.
• Bedtime hypertension therapy is at least as safe, and with similar patient compliance and adherence, than usual upon-waking therapy.

CME INDIA Tail Piece

• Other prospective trials like “The HOPE trial” established that add-on bedtime ramipril, relative to placebo, therapy significantly reduced the primary outcome variables of CVD death, myocardial infarction, and stroke in a cohort of 9297 already treated high-risk individuals aged >_55 years.
• Interestingly, a small ABPM sub-study found profound lowering of the night-time SBP/DBP by an average of 17/8 mmHg (P< 0.001 compared with placebo) that translated into significant increase by 8% of the sleep-time relative BP decline.
• The Syst-Eur trial, involving 4695 elderly persons with isolated SBP hypertension diagnosed by OBPM alone, found that evening CCB nitrendipine therapy, compared with placebo, reduced the primary endpoint of stroke by 42% (P= 0.003), CVD mortality by 27% (P= 0.07), and total CVD outcomes by 31% (P < 0.001).13
• The SystChina trial of almost identical protocol reported that evening treatment reduced stroke by 38% (P= 0.01), total mortality by 39% (P= 0.003), CVD mortality by 39% (P= 0.003), and total CVD outcomes by 37% (P = 0.004).

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