Management of CVD in Indian Settings and Scope of Amlodipine and Atenolol Fixed-Dose Combination-Review

Disease burden in India- According to World Health Organization, India accounts for one-fifth of these CVD-related fatalities globally, particularly among the young. According to the Global Burden of Disease research findings, India has an age-standardized CVD mortality rate of 272 per 100,000 people, much higher than the global average of 235. (2)

Analyzing the unique features of CVD among Indians: Reasons to worry- CVDs strike Indians a decade earlier than in western countries. The cause of concern in Indian CVD patients includes early age of onset, quick progression, and high mortality rate. (2) Indians are also known to have a high incidence of coronary artery disease (CAD); alarmingly, the traditional risk factors fail to explain this higher risk. (2)

CVDs and Hypertension: Decoding the Undeniable link

With estimates revealing that 16% of CAD, 21% of peripheral vascular disease (PVD), 24% of acute myocardial infarction (AMI), and 29% of strokes are attributed to hypertension (2), it is established to be one of the major modifiable risk factors associated to CVDs.

Several studies have indicated that strict blood pressure management is essential to decrease clinical cardiovascular endpoints significantly. According to the Framingham Heart Study, a 2-mm Hg drop in average diastolic blood pressure (DBP) can reduce the incidence of stroke and transient ischemic attacks by 14% and coronary artery disease by 6%. Another meta-analysis found that prolonged DBP reductions of 5, 7.5,and 10 mm Hg were linked with 34%, 46%, and 56% fewer strokes and 21%, 29%, and 37% reduced incidences of coronary heart disease, respectively. (3)

With research highlighting the prominent link between hypertension and CVDs, and 50% of CVD patients require more than one drug for target blood pressure control, the focus has been on dual therapy, combining different pharmacological classes, for quite some time now. Experts advocate that the first-line combination therapy selection in managing CVD patients should be individualized, depending on the targeted pharmacological activities, co-morbidities, and adverse effects. (3)

Managing hypertension & CVDs: How do Combination therapies work?

Combining different antihypertensives is an accepted and widely advocated therapeutic approach to control blood pressure. Notable advantages of combination therapy over monotherapy include a synergistic impact of each component drug's therapeutic effects and a reduction in side effects due to a lower dose of each drug. (4)

Amlodipine is a charged dihydropyridine-type (DHP) calcium channel blocker (CCB) indicated for the treatment of high blood pressure, heart attacks, and chest pain (angina). In contrast, Atenolol is a relatively long-acting (24 hours) beta-blocker.

Amlodipine has a gradual onset of action and prolonged half-life that causes little or no reflex tachycardia. These properties improve its efficacy in suppressing ischemia alone and with a beta-blocker. Moreover, its abilities to prevent activation of counter-regulatory mechanisms, slow the progression of atherosclerosis, confer antioxidant properties and enhance nitric oxide (NO) production make it a great therapeutic option in hypertension and hypertensive patients CVDs. (4)

Studies have shown that combining beta-blockers and DHP-CCBs is more effective in alleviating angina. On these lines, a meta-analysis revealed that the combination of a calcium antagonist and a beta-blocker was statistically more successful than either monotherapy, based on the results of exercise testing. (5)

Interestingly, research also reveals that side effects were reduced by adding amlodipine to a beta-blocker, thus confirming a lower side effect profile than the individual drugs. (4)

Recognizing its potency, the Cardiological Society of India guidelines recommend beta-blockers and CCBs as the first-line medicines for long-term symptom management and heart rate control in angina. (5)

Positioning Amlodipine-Atenolol combination- Clinical Benefits

Amlodipine with Atenolol bestows a good option for combining a beta blocker and DHP-CCB, two classes of agents with proven cardiovascular benefits and for better blood pressure control. (4)

Their unique features are summarized below:

Better efficacy: Combining two drugs with distinct modes of action results in an antihypertensive effect that is two to five times stronger than monotherapy. Increased monotherapy dosage decreases coronary events by 29% and cerebrovascular events by 40%, whereas combining two antihypertensives with distinct mechanisms of action reduces coronary events by 40% and cerebrovascular events by 54%. As a result, using a combination treatment protects a target organ better than raising the dose of monotherapy. (4)

Patient compliance: Studies analyzing patient compliance with more than one drug therapy (taken separately) reveal that discontinuation and non-adherence increased the risk of CVD events and mortality. Patient-level hurdles reported were high drug costs, a distaste for many drugs, the intricacy of regimens, and no apparent advantages of taking medication while side effects were prominent. (6) These challenges, to a large extent, are overcome by combination therapies.

Reduced side effect profile: The individual negative effects of amlodipine and atenolol have been demonstrated to be reduced when the two medicines are combined. For example, amlodipine's systemic vasodilation-induced reflex sympathetic activity negates the heart rate-lowering impact of atenolol. (7) Atenolol's coronary vasoconstrictor action is attenuated by amlodipine's coronary vasodilation (8). Balancing each other's side effects makes it one of the clinically relevant combinations for hypertensive CVDs.

Young Indian Hypertensives – Sympathetic Overactivity and Need for Beta Blockers (9)

In a survey aimed to understand the Indian clinician’s perspective on the approach to the management of hypertension in young adults, results revealed that 57.4% of respondents considered increased heart rate and increased systolic blood pressure as sympathetic over activity markers in young hypertensives.74.5% of physicians in India chose beta-blockers as part of the antihypertensive prescription in young hypertensive people, based on the rationale of sympathetic over activity.

Estimates also highlight that sympathetic overactivity prevails in approximately 62% of newly diagnosed hypertensive patients in India. Alarmingly, a chronically raised sympathetic nerve activity, independent of blood pressure, is a powerful predictor of myocardial infarction.

Beta-blockers are justified due to their simultaneous efficacy in regressing and stabilizing coronary atheromatous plaque and their attenuating effects on raised sympathetic activity.

Key takeaways-

• India is facing a sharp rise in cardiovascular diseases. Hypertension has now emerged as a major modifiable risk factor in CVDs.
• To achieve the greatest reduction in clinical cardiovascular endpoints in hypertensive patients, blood pressure must be effectively controlled.
• Combination treatment is advantageous since several variables contribute to hypertension, and controlling blood pressure with a single medication targeting a single pathway may be daunting.
• Combining two classes makes them available in a convenient dosage regime, reduces the dose of each component, reduces adverse effects, and improves compliance.
• Atenolol-amlodipine drug therapy, working synergistically via multiple pathways, has exhibited promising results in managing CVDs.

References

1. Prabhakaran, D., Jeemon, P., & Roy, A. (2016). Cardiovascular diseases in India: current epidemiology and future directions. Circulation, 133(16), 1605-1620.

2. Kumar, A. S., & Sinha, N. (2020). Cardiovascular disease in India: a 360-degree overview. Medical Journal, Armed Forces India, 76(1), 1.

3. Kalra, S., Kalra, B., & Agrawal, N. (2010). Combination therapy in hypertension: An update. Diabetology & metabolic syndrome, 2(1), 1-11.

4. Diksha Sharma, Dinesh Kumar Mehta, Karun Bhatti, Rina Das, Ram Mohan Chidurala. Amlodipine And Atenolol: Combination Therapy Versus Monotherapy Reducing Blood Pressure - A Focus On Safety And Efficacy. Research J. Pharm. and Tech 2020; 13(6): 3007-3013. doi: 10.5958/0974-360X.2020.00532.6

5. Mishra, S., Ray, S., Dalal, J. J., Sawhney, J. P. S., Ramakrishnan, S., Nair, T., ... &Bahl, V. K. (2016). Management standards for stable coronary artery disease in India. Indian Heart Journal, 68, S31-S49.

6. Yusuf, S., Attaran, A., Bosch, J., Joseph, P., Lonn, E., McCready, T., ... & Xavier, D. (2013). Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges. European Heart Journal, 35(6), 353-364.

7. Woodmansey PA, Stewart AG, Morice AH, Channer KS. Amlodipine in patients with angina uncontrolled by atenolol. A double-blind placebo-controlled cross-over trial. Eur J Clin Pharmacol. 1993;45(2):107-11

8. Davies RF, Habibi H, Klinke WP, et al. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS)Investigators. J Am Coll Cardiol. 1995 Mar 1;25(3):619-25

9. Jadhav, U., Tiwaskar, M., Khan, A., Kalmath, B. C., Ponde, C. K., Sawhney, J., ... & Chopra, V. K. (2021). Hypertension in Young Adults in India: Perspectives and Therapeutic Options amongst Clinicians in a Cross-Sectional Observational Study. The Journal of the Association of Physicians of India, 69(11), 11-12.