Amlodipine and Cardiovascular outcomes in Hypertensive patients: What Meta-analysis says
A major risk factor for cardiovascular disease is hypertension. A multitude of drugs, including calcium channel blockers (CCBs), β-blockers, angiotensin receptor blockers (ARBs), Angiotensin-converting enzyme inhibitors (ACEIs) as well as Diuretics have been used as monotherapy or in combination to treat hypertension (1). Initially used for coronary heart disease (CHD), CCBs over the past few years has gained wide recognition for their efficacy in the treatment of hypertension (HTN). CCBs are also being used for angina, peripheral vascular disease, and certain arrhythmic conditions apart from Hypertension (2).
Amlodipine:
One of the most common Calcium Channel Blockers that is extensively used to treat both angina and hypertension is Amlodipine. Developed under the direction of Dr Simon Campbell, it is a synthetic dihydropyridine and a long-acting calcium channel blocker (as besylate, mesylate or maleate) with antihypertensive and antianginal properties. It inhibits the influx of extracellular calcium ions into myocardial and peripheral vascular smooth muscle cells, thereby preventing vascular and myocardial contraction and resulting in dilatation of the main coronary and systemic arteries (3).
Amlodipine is generally prescribed on a once-daily basis because of its long half-life starting with a dose of 5 mg to a maximum daily dose of 10 mg. It has a gradual onset of action and no significant reflex neuroendocrine activation, and if discontinued, BP generally returns to baseline over one week without any dangerous rebound elevations (4).
Various trials in the past have evaluated the cardiovascular outcomes of amlodipine-based regimens. Some of the most popular ones include the ALLHAT, ACCOMPLISH, AASK, and ASCOT trials
The ALLHAT Trial or the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial was one of the early clinical trials performed between 1993 to 2002 and evaluated the incidence of fatal coronary heart disease or non-fatal myocardial infarction in high-risk hypertensive patients in the United States and Canada treated with a strategy based on a CA (Amlodipine), an ACE inhibitor (lisinopril) or an alpha-blocker (doxazosin), in comparison with a thiazide diuretic (chlorthalidone) (9) (10)
Another trial, the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension or ACCOMPLISH Trial was performed between 2003 and 2008 (11) and was a Prospective, Multinational, Multicenter Trial to Compare the Effects of Amlodipine/Benazepril to Benazepril and Hydrochlorothiazide Combined on the Reduction of Cardiovascular Morbidity and Mortality in Patients With High-Risk Hypertension.
The African-American Study of Kidney Disease and Hypertension (AASK) Trial published in 2007 was also a vital trial that evaluated the effect of blood pressure and antihypertensive drug therapy on the rate of decline of renal function in participants with mild-to-moderate chronic renal insufficiency caused by hypertension.
The Anglo-Scandinavian Cardiac Outcomes Trial or ASCOT trial was an essential trial that alsonrevealed the benefit of amlodipine/perindopril for blood pressure control.
Besides these four relevant trials, many studies have been conducted in the past to analyze the various aspects of Amlodipine and its comparison with other molecules.
Nagoya Heart study compared Valsartan and Amlodipine to reduce cardiovascular events in hypertensive patients with glucose intolerance. They found that a significantly lower incidence of heart failure was seen in the Valsartan group than in the amlodipine group, but other components and all-cause mortality were not significantly different between the 2 groups (5).
Another study by Carlos Ferrario et al studied the clinical and economic outcomes associated with fixed drug combinations of Amlodipine with other drug combinations like olmesartan (OM), benazepril (BEN), and angiotensin II receptor blockers (ARB). They found that fixed drug combinations of AML/OM were associated with a greater likelihood of adherence and lower overall costs than with AML/BEN and AML/ARB, and lower risk of cardiovascular event composite versus AML/ARB (6).
A meta-analysis by Wang et al using data on the treatment-induced changes in intraindividual Blood Pressure Variability (BPV) available from randomized clinical trials involving Amlodipine and other comparators showed that Amlodipine was more effective in minimizing visit to visit BPV (7,8).
Most of the trials have come to a common conclusion that
Amlodipine can be safely used in high-risk cardiac patients and is associated with benefits for all major cardiovascular endpoints and total mortality.
With so many trials on the formulation, In 2014, Seung Ah Lee from Seoul National University Hospital and et al. published a meta-analysis comparing the effects of amlodipine besylate with other non-CCB antihypertensive therapies regarding the cardiovascular outcome in hypertensive patients. They used data from large-scale, comparative, long-term outcome trials and evaluated the outcomes.
Methodology:
Using PubMed searches, various studies were identified using the key terms like "stroke or myocardial infarction" or "coronary heart disease" or "heart disease" or "cardiovascular disease" and "hypertension" and "amlodipine." The inclusion criteria for meta-analysis were a randomized controlled trial published in a peer-reviewed journal, the inclusion of patients with hypertension, comparison of Amlodipine with another antihypertensive drug, assessment of cardiovascular events, follow-up of 1 year or longer, and a sample size of 100 or more. Studies that examined only surrogate endpoints for cardiovascular diseases, studies with primary outcomes other than cardiovascular disease, and studies that excluded hypertensive subjects were not included. The searches were performed up to November 2011. Out of 370 articles, 8 studies met the inclusion criteria but 1 was excluded from these and 7 were taken for the meta-analysis.
Analysis:
The studies were divided into two arms. The first group contained studies that compared amlodipine-based regimens with non-CCB-based regimens such as diuretics (ALLHAT/chlorthalidone and ACCOMPLISH) or ß-blockers (AASK/metoprolol and ASCOT). The second group contained studies that compared amlodipine-based regimens with RAS- blocking regimens such as ACE inhibitors (AASK/ramipril and ALLHAT/lisinopril) or ARBs (IDNT, VALUE, and CASE-J). The major cardiovascular events included coronary heart disease (CHD), stroke, CHF, and other cardiovascular disease mortalities. Statistical calculations and graphs were produced using Cochrane Review Manager (RevMan) software, ver. 5.0.
Results:
87,257 patients were included from all the studies. The mean duration of follow-up was 4.6 years (range, 3 to 6 years). The mean age of the patients was 66 years, and out of this, 31% were women. About 39% of the patients had diabetes mellitus, and 18% were smokers. The results of the analysis were seen as impacts on various conditions including the following
Myocardial Infarction:
The risk of MI was significantly decreased with amlodipine-based regimens compared with other drugs (OR, 0.91; 95% CI, 0.84 to 0.99; p = 0.03).
The risk reduction of amlodipine-based therapy was similar to that of the non-CCB-based regimen, but they were not statistically significant due to decreased sample size.
Stroke:
The risk of stroke was significantly decreased with amlodipine-based regimens compared with other antihypertensive drugs (OR, 0.84; 95% CI, 0.79 to 0.90; p< 0.00001).
Heart Failure:
The risk of heart failure seemed to increase with marginal significance with amlodipine-based regimens compared with other antihypertensive drugs (OR, 1.14; 95% CI, 0.98 to 1.31; p = 0.08).
Combined major cardiovascular events:
Amlodipine-based regimens showed a 10% risk reduction, which was statistically significant (OR, 0.90; 95% CI, 0.82 to 0.99; p = 0.02) and showed lower risk compared with non-CCB- based conventional regimens.
Total and cardiovascular mortality:
Amlodipine-based regimens demonstrated a significant risk reduction compared with other antihypertensive drugs (OR, 0.95; 95% CI, 0.91 to 0.99; p = 0.01). The risk reduction was greater when compared with non-CCB-based conventional regimens but not increased when compared with RAS-blocking regimens.
The researchers with the Meta-Analysis concluded that
Amlodipine-based regimens reduced the risk of total cardiovascular events and mortality compared with non-calcium channel blocker antihypertensive therapies.
In particular, through the meta-analysis, researchers put forth that amlodipine-based regimens reduced the risk of myocardial infarction and stroke, reduced the risk of total cardiovascular events by 10%, and the risk of total mortality by 5% compared with non-CCB antihypertensive therapy.
They further added that Amlodipine had a protective effect against myocardial infarction and stroke.
The authors also noted that CHF incidence seemed to be increased with Amlodipine compared with ACE inhibitors or ARBs but was comparable to that with ß-blockers and diuretics. The Meta-Analysis further put forward a clear conclusion that
Amlodipine can be safely used in high-risk cardiac patients and is associated with benefits for all major cardiovascular endpoints as well as total mortality.
The unique features of this Meta-analysis were:
- Minimizing the confounding effect of variability of treatment due to the substantial difference between DHPs and non-DHP CCBs.
- The study was limited to data from actively controlled trials to minimize the effect of blood pressure reductions observed in placebo-controlled trials.
- Only trials that evaluated long term outcomes and having clearly defined primary and secondary endpoints were enrolled.
References:
1. Fares H, DiNicolantonio JJ, O'Keefe JH, et al Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes Open Heart 2016;3:e000473.
2. Triggle DJ. Calcium channel antagonists: clinical uses—past, present and future. Biochem Pharmacol 2007;74:1–9
3. National Center for Biotechnology Information. PubChem Compound Summary for CID 2162, Amlodipine. https://pubchem.ncbi.nlm.nih.gov/compound/Amlodipine.
4. Abernethy DR. Pharmacokinetics and pharmacodynamics of Amlodipine. Cardiology 1992;80(Suppl 1):31–6.
5. Comparison Between Valsartan and Amlodipine Regarding Cardiovascular Morbidity and Mortality in Hypertensive Patients With Glucose Intolerance: NAGOYA HEART Study [retraction of hypertension. 2012 Mar;59(3):580-6]. Hypertension. 2018;72(3):e37-e38.
6. Ferrario, C. M., Panjabi, S., Buzinec, P., & Swindle, J. P. (2013). Clinical and economic outcomes associated with amlodipine/renin–angiotensin system blocker combinations. Therapeutic Advances in Cardiovascular Disease, 27–39.
7. Kollias A, Stergiou GS, Kyriakoulis KG, Bilo G, Parati G. Treating Visit-to-Visit Blood Pressure Variability to Improve Prognosis: Is Amlodipine the Drug of Choice?. Hypertension. 2017;70(5):862-866.
8. Wang JG, Yan P, Jeffers BW. Effects of Amlodipine and other classes of antihypertensive drugs on long-term blood pressure variability: evidence from randomized controlled trials.J Am Soc Hypertens. 2014; 8:340–349.
9. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group; The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997.
10. https://clinicaltrials.gov/ct2/show/NCT00170950https://clinicaltrials.gov/ct2/show/NCT00170950
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