Amlodipine as First-line Antihypertensive-Review of Indian Evidence

Revelation of the Alarming Hypertension Statistics in India:

Hypertension (HTN) contributes to 1.6 million deaths annually in India, making HTN the most significant contributor to the burden of disease and mortality. With an overall prevalence of 29.8%, 57% of stroke-related deaths and 24% of coronary heart disease-related deaths have been linked to HTN. (2)

Research consistently highlights that late or inefficient therapy often results in permanent and irreversible damage to the cardiovascular (CV) system. (1) An adult prevalence of 30.7% was found in a recent nationwide survey of 24 Indian states and union territories, indicating that nearly one in three respondents had hypertension. (3) Alarmingly, less than half of those with hypertension have their blood pressure (BP) under control. (1) Under such grim scenarios, improved diagnosis and optimal management of HTN is a public health necessity in India and brings out the need for critical and cost-effective primary care interventions. (2)

Facing The Crisis -Need for Early Diagnosis & Treatment

Recognized as a major modifiable risk factor for cardiovascular and renal disease in India, early detection and treatment of hypertension would reduce a significant burden of cardiac (congestive heart failure, coronary artery disease), cerebrovascular (ischemic and hemorrhagic stroke), and renal (chronic kidney disease) morbidities. Despite this, low awareness levels are widely prevalent among Indians, and misdiagnosis remains a challenge among physicians. (2) In India, 34.6% of hypertensives are aged <45 years, putting young Indians at an increased risk of premature mortality due to cardiovascular disorders. (4)

Managing Hypertension: Role of Calcium Channel Blockers-

Calcium channel blockers (CCBs) were introduced to treat coronary heart disease (CHD) over four decades ago but they quickly earned widespread acceptance for their effectiveness in hypertension. (5)

Global landmark trials like ALLHAT, VALUE, ASCOT, and ACCOMPLISH recommend calcium channel blockers-based therapy for managing low and high CV risk hypertensive patients. (1) Affirming this, CCBs are recommended as one of the “first line” antihypertensive medications in the major hypertension guidelines. (1,6)

CCBs inhibit the inflow of calcium ions into vascular and cardiac smooth muscle cells, facilitating the heart to pump blood more efficiently. Amlodipine, a CCB, exerts its pharmacological activity by blocking the voltage-gated calcium ion channels (1)

Position of Amlodipine in Managing Hypertension –

Amlodipine is a long-acting, lipophilic, third-generation dihydropyridine (DHP) CCB with a well-demonstrated history of safety and efficacy in lowering blood pressure and the risk of cardiovascular events. (1) It has a high vascular selectivity that reduces peripheral resistance while preserving myocardial contractility. (4) Amlodipine reduces the risk of cardiovascular events and all-cause mortality, unlike non-CCB antihypertensives. (7) The fact that when Amlodipine is withdrawn, blood pressure usually returns to baseline within a week, with no harmful rebound increase in BP, affirms its clinical utility. (5)

Statistics reveal that among the CCBs, Amlodipine is preferred by 75.7% of Indian physicians, making it a widely advocated anti-hypertensive drug across the country. The same study highlighted that prescribing amlodipine as monotherapy or add-on therapy reduced overall mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) by 13.6 mmHg and 8.0 mmHg, respectively. (4)

Testimonies of Indian Scientific Evidence-

• Twenty-Four Hours BP Control by Amlodipine- A review (1) aimed to assess the efficacy of Amlodipine in controlling 24-hour BP and minimizing blood pressure variability (BPV) throughout the day, revealed that Amlodipine is a powerful, well-tolerated, and safe antihypertensive agent and can block all the subtypes of CCBs such as L-, N-, P-, Q-, R-, and T-type calcium channels. The team also elaborated that due to its efficacy in controlling 24-hour BP, minimizing BP variability, and reducing the risk of cardiovascular complications, Amlodipine is widely used alone or as a critical component of combination therapy.
• Convenient dosing- Amlodipine has the most extended half-life of 30 to 50 hours, thus allowing for a once-daily dosage profile compared to nifedipine and other dihydropyridines (DHP) drugs. (1) Due to a gradual onset of action of Amlodipine (it binds to the target receptors in a slow and sustained manner), it causes no significant reflex neuroendocrine activation. (6)
• Cost-Effectiveness of Amlodipine-Based Treatment Regimen -In India, the cost of drugs often dictates their use and patient acceptance. Amlodipine, combined with monotherapy, has been confirmed to be one of the most cost-effective drugs in India. (1,2 8)
• Potent BP Lowering Across Age Groups- A study (4) aimed to provide real-world evidence regarding the effectiveness of amlodipine as monotherapy or in combination with other antihypertensive drugs (AHDs) in Indian patients with essential hypertension. They concluded that Amlodipine prescribed as monotherapy or add-on therapy in routine clinical practice significantly reduced blood pressure in HTN (mild to moderate hypertension) patients across age groups, i.e. <45 years, 45-65 years, and >65 years.
• Amlodipine and Atherosclerosis- Amlodipine has a potential advantage in improving markers of atherosclerosis. It inhibits the generation of free radicals, preventing oxidative damage to the lipid bilayer. The PREVENT trial looked at the effect of Amlodipine on atherosclerotic progression in patients who already had CAD and highlighted that Amlodipine attenuated the progression of carotid artery atherosclerosis. The team further elaborated that the drug also decreased coronary revascularizations (53 versus 86, HR 0.57 [0.41 to 0.81]) compared to placebo. (9)
• Amlodipine and Angina-Amlodipine's antianginal effectiveness is mediated by amlodipine-induced coronary artery dilatation and a decrease in total peripheral resistance, which reduces the incidence of symptomatic angina and silent MI. (9)
• Amlodipine has also been documented to slow the progression of chronic kidney disease (CKD). (9)
• Drug safety-Peripheral edema is the most reported side event that interferes with Amlodipine compliance. If the drug is taken at bedtime this side effect may be reduced. Other reported adverse effects include dizziness, exhaustion, headache, palpitations, and nausea, but rarely warrant discontinuation. (5)

Recommended Dosage Regimen- In hypertensives, a starting dose of 5 mg of Amlodipine is usually recommended, with a maximum daily dose of 10 mg. In elderly patients and those with severe hepatic impairment, a starting dose of 2.5 mg is recommended. (5)

Place of Amlodipine in Hypertension Guidelines-

• For adults with hypertension requiring pharmacological treatment, WHO recommends a long-acting dihydropyridine CCBs as initial therapy. (10)
• Amlodipine is on the WHO's list of essential medications and is documented as one of the health system's safest and most effective medicines. (1)
• According to guidelines from the Ministry of Health and Family Welfare (MoHFW), India, a long-acting calcium channel blocker can be used as the initial antihypertensive drug without any associated clinical conditions. (2)
• According to the 2019 Indian Guidelines on Hypertension (IGH-IV), CCBs are among the preferred agents for the treatment of hypertension among adults (above the age of 60 years). Combination therapy is encouraged, with CCBs in combination with angiotensin converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) being considered a first-line combination. (11)

KEY POINTERS-

• Hypertension-associated morbidity and mortality in India are very high. Despite the striking prevalence and disease outcomes attributed to hypertension, India's awareness, optimum treatment, and control of hypertension remain poor.
• Among the various antihypertensive drug classes, CCBs, either as monotherapy or in combination with other antihypertensive drugs, are widely accepted in India.
• Amlodipine is a decades-old, tried-and-tested calcium channel blocker that successfully manages blood pressure while preserving circadian rhythm and lowering the risk of CV and cerebrovascular problems.
• Amlodipine's effectiveness and safety as a monotherapy and combination treatment have been widely tested and validated across broad age groups in global and Indian studies.
• The unique features of Amlodipine make it an excellent first-line anti-hypertensive.

REFERENCES

1. Nair, T., Kumar, A. S., Unni, T. G., Tiwaskar, M. H., Sharma, S., & Gaurav, K. 24-Hour Blood Pressure Control with Amlodipine: A Review of the Current Scenario. Journal of Cardiac Critical Care. 2022. TSS 6(01), 059-068. https://doi.org/ 10.1055/s-0042-1750195. ISSN 2457-0206

2. Ministry of Health and Family Welfare. Screening, diagnosis, assessment, and management of primary hypertension in adults in India. https://nhm.gov.in/images/pdf/guidelines/nrhm-guidelines/stg/Hypertension_full.pdf.[Accessed 30th August 2022]

3. Ramakrishnan S, Zachariah G, Gupta K, Shivkumar Rao J, Mohanan PP, Venugopal K, Sateesh S, Sethi R, Jain D, Bardolei N, Mani K, Kakar TS, Kidambi B, Bhushan S, Verma SK, Bhargava B, Roy A, Kothari SS, Gupta R, Bansal S, Sood S, Nath RK, Tyagi S, Gupta MD, Girish MP, Kalra IPS, Wander GS, Gupta S, Mandal S, Senguttuvan NB, Subramanyam G, Roy D, Datta S, Ganguly K, Routray SN, Mishra SS, Singh BP, Bharti BB, Das MK, Kumar S, Goswami KC, Bahl VK, Chandra S, Banerjee A, Guha S, Deb PK, Chopra HK, Deedwania P, Seth A; CSI-Great India BP Campaign Investigators. Prevalence of hypertension among Indian adults: Results from the great India blood pressure survey. Indian Heart J. 2019 Jul-Aug;71(4):309-313. doi: 10.1016/j.ihj.2019.09.012. Epub 2019 Sep 18. PMID: 31779858; PMCID: PMC6890959.

4. Khan MY, Pandit S, Ray S, Mohan JC, Srinivas BC, Ramakrishnan S, Mane A, Mehta S, Shah S. Effectiveness of Amlodipine on Blood Pressure Control in Hypertensive Patients in India: A Real-World, Retrospective Study from Electronic Medical Records. Drugs Real World Outcomes. 2020 Dec;7(4):281-293. doi: 10.1007/s40801-020-00211-w. PMID: 32901435; PMCID: PMC7581658

5. Fares H, DiNicolantonio JJ, O'Keefe JH, Lavie CJ. Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart. 2016 Sep 28;3(2):e000473. doi: 10.1136/openhrt-2016-000473. PMID: 27752334; PMCID: PMC5051471.

6. Khan MY, Shetty S, Oomman A, Jain P, Gaurav K. Amlodipine and Landmark Trials: A Review. J Cardiol and Cardiovasc Sciences. 2021;5(3):1-8

7. Lee SA, Choi HM, Park HJ, Ko SK, Lee HY. Amlodipine and cardiovascular outcomes in hypertensive patients: meta-analysis comparing amlodipine-based versus other antihypertensive therapy. Korean J Intern Med. 2014 May;29(3):315-24. doi: 10.3904/kjim.2014.29.3.315. Epub 2014 Apr 29. PMID: 24851066; PMCID: PMC4028521.

8. Limaye, Dnyanesh & Kale, Mayur & Chitre, Neha & Deshapande, D. & Desai, Raj & Limaye, Vaidehi & Fortwengel, Gerhard. (2016). Cost-effectiveness Study of Antihypertensive Drugs in Mumbai, India. Current Therapeutic Research. 78. S2. 10.1016/j.curtheres.2016.05.005.

9. Tiwaskar M, Langote A, Kashyap R, Toppo A. Amlodipine in the Era of New Generation Calcium Channel Blockers. J Assoc Physicians India. 2018 Mar;66(3):64-9. PMID: 30341872.

10. World Health Organization. (‎2021)‎. Guideline for the pharmacological treatment of hypertension in adults: web annex A: summary of evidence. World Health Organization. https://apps.who.int/iris/handle/10665/344384. License: CC BY-NC-SA 3.0 IGO [Accessed 30th August 2022].

11. Shah SN, Munjal YP, Kamath SA, Wander GS, Mehta N, Mukherjee S, Kirpalani A, Gupta P, Shah H, Rohatgi R, Billimoria AR, Maiya M, Das MK, Goswami KC, Sharma R, Rajapurkar MM, Chawla R, Saboo B, Jha V. Indian guidelines on hypertension-IV (2019). J Hum Hypertens. 2020 Nov;34(11):745-758. doi: 10.1038/s41371-020-0349-x. Epub 2020 May 19. PMID: 32427886.