Summary

Dr. Sundeep Mishra writes that several factors need to be taken into account while prescribing therapy for hypertension, diurnal variation of BP being one such variable for which the drug Diltiazem proves particularly effective.

Hypertension is a chronic condition with significant morbidity; it approximately accounts for about 54% of strokes and 47% of coronary heart disease worldwide. Although clinicians have a number of safe and well-tolerated antihypertensive agents that have shown to reduce the risk of adverse CVD events at their disposal, there are several nuances to effective anti-hypertensive Rx.

A diurnal variation in BP values is one such variable which should be considered while choosing an effective therapy for hypertension.

Diltiazem vs. Ramipril

Angiotensinogen converting enzyme inhibitors (ACE-I) are now considered first line Rx in the management of hypertension. A double-blind, titration-to-effect trial was conducted to compare the effects of a graded-release delivery system of diltiazem (diltiazem HCL extended release tablets) vs. ramipril on BP, heart rate, and the heart rate-systolic BP product during the first 4 h after awakening, both dosed at bedtime.

About 261 men and women having an untreated sitting diastolic BP of 90 to 109 mm Hg and ambulatory daytime diastolic BP of 85 to 109 mm Hg were enrolled in the trial. The patients were randomised to receive either diltiazem extended release (ER) tablets each evening (240 mg titrated to 360 mg and to 540 mg) or ramipril each evening (5 mg titrated to 10 mg and to 20 mg).

Early morning assessments of BP, heart rate, and the heart rate-systolic BP product were performed using 24-hour ambulatory recordings after 10 weeks of therapy. It was reported that in each therapeutic group, 76% of patients were titrated to the highest possible dose.

1. After 10 weeks of treatment, reductions in early morning BP by diltiazem ER tablets were significantly greater (‑18/‑15 mm Hg) than reductions by ramipril (-13/-8 mmHg).
2. Diltiazem ER tablets also led to greater reductions in morning heart rate and the heart rate-pressure product compared to ramipril.
3. Reductions in mean 24 hour diastolic BP, heart rate, and the rate-pressure product were greater in patients treated with diltiazem ER tablets compared to ramipril, while reductions in 24 hour systolic BP were similar in each group.
4. The observed adverse effects were not serious, and incidences were similar for both the treatment groups.

Thus, it could be concluded that bedtime administration of diltiazem ER, an agent designed to parallel the circadian rhythm of BP and heart rate, led to significantly greater early morning haemodynamic effects compared to the angiotensin-converting enzyme inhibitor ramipril.

Diltiazem vs. diuretics & beta blockers

It fares equally well as compared to classical anti-hypertensive agents like diuretics and beta-blockers also. A prospective, randomised, open, blinded endpoint study was conducted to compare the effects of diltiazem with that of diuretics, β-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients.

The study included n=10,881 patients aged 50 to 74 years, from health centers who had diastolic BP of 100 mm Hg or more. The patients were randomly assigned to either a diltiazem-based regimenor conventional antihypertensive treatment withdiuretics, β‑blockers, or both. In diltiazem group:

• Step 1- Short-acting diltiazem (180–360mg), later replaced by long acting formulation
• Step 2- Angiotensin converting enzyme (ACE) inhibitor was added
• Step 3- A diuretic or α-blocker was added to the ACE inhibitor
• Step 4- Any other anti-hypertensive was added

Similarly, in diureticand β-blocker group:

• Step 1 was a thiazide diuretic ora α-blocker
• Step 2 the two were combined
• Step 3 an ACE inhibitor or α-blocker was added
• Step 4 any other antihypertensive compound could be added except a calcium antagonist

The combined primary endpoint was fatal and non‑fatal strokeand other cardiovascular death. It was reported, that systolic and diastolic BP were effectively lowered in diltiazem vs. diuretic and β-blocker groups (20.3/18.7 vs. 23.3/18.7 mm Hg).

A primary endpoint occurred in 403 patients in the diltiazem group vs. 400 in the diuretic and β-blocker group (16.6 vs. 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87–1.15]). Fatal and non‑fatal stroke occurred in 159 patients in the diltiazem group vs. 196 patients in the diuretic and β‑blocker group (6.4 vs. 7.9 events per 1000 patient-years; 0.80 [0.65–0.99]).

Thus, from the study it could be concluded that diltiazem is as effective as treatment based on diuretics, β-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death.

Diltiazem stands up to both older as well as newer anti-hypertensive agents and because of its unique properties like diurnal control of blood pressure and heart rate reducing properties, it should be considered as first line drug in the management of at least tachycardia associated hypertension.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.