Amlodipine: a pharmacoeconomic review

Abstract

Objectives. To review the pharmacoeconomic impact of the use of amlodipine in coronary artery disease (CAD) patients.

Methods. A review of the available outcome trials evaluating the clinical effectiveness of amlodipine in hypertensive patients or in patients with CAD or diabetic nephropathy was carried out to identify pharmacoeconomic studies that quantified the economic impact of using amlodipine instead of another treatment.

Results. A combined analysis of two trials comparing angiotensin receptor blockers (ARBs) with a calcium channel blocker amlodipine suggested that amlodipine provided more protection against stroke and myocardial infarction than ARBs. In addition, in keeping with previous meta-analyses, calcium channel blockade with amlodipine also prevented more stroke than angiotensin-converting enzyme inhibitors and old drug classes.

Pharmacoeconomic analysis conducted in the US and Europe demonstrated that the use of amlodipine resulted in fewer hospitalisations and the need for fewer invasive surgical procedures in the short and long term and at a modest incremental cost. The use of amlodipine resulted in improved clinical outcomes as well as slight savings in cost.

Conclusions. Amlodipine is not only cost effective, but predicted to be cost saving when compared with usual care, warranting its consideration as an agent of choice in patients with CAD.

Keywords::

• Amlodipine
• coronary artery disease
• cost effectiveness

Introduction

Cardiovascular disease (CVD) is the leading cause of death in industrialised countries^1–3. Each year it accounts for over 4 million deaths in Europe: 49% of all fatal events. About half of all CVD deaths (around 2 million per year) are the result of coronary artery disease (CAD)³, which is today the most frequent cause of mortality and morbidity, notwithstanding a decline in recent decades^4,5.

The benefits of antihypertensive drugs for the prevention of cardiovascular mortality and morbidity are well established^6,7.

Antihypertensive drugs have a variety of potentially beneficial properties that might favourably affect cardiovascular event rates⁸.

In a recent editorial^9,10, a combined analysis of two trials^11,12 comparing angiotensin receptor blockers (ARBs) with a calcium channel blocker, amlodipine, suggested that amlodipine provided more protection against stroke and myocardial infarction than ARBs. In addition, in keeping with previous meta-analyses^6,7,13–15, calcium channel blockade by amlodipine also prevented more stroke than angiotensin-converting enzyme (ACE) inhibitors and older drug classes (diuretics and β-blockers)^9,10.

Several studies have also shown that calcium channel blockers are able to inhibit platelet aggregation^16–18 and to exert inhibitory effects on smooth muscle cell proliferation¹⁹. As a consequence, these agents can have beneficial effects on restenosis prevention: results of a meta-analysis²⁰ showed a 30% reduction in the risk of restenosis in patients treated with these calcium channel blockers. The authors of the meta-analysis concluded by saying that the relatively low toxicity and cost of these agents could possibly translate the reduction in angiographic restenosis into meaningful clinical benefits¹⁸.

ISSN 1369-6998 print/ISSN 1941-837X online © Informa UK LtdDOI: 10.3111/13696990802525266http://www.informapharmescience.com/JMEThe epidemiological and economic panorama of CAD and its consequences highlight the need for appropriate medical treatment. Advances in medical practice have improved clinical outcomes, but the need still remains to find forms of treatment that can help minimise repeated hospitalisation and future revascularisation procedures¹.

Clinical effectiveness of amlodipine

Because of the large number of trials that involve amlodipine as a treatment, outcome trials were selected which involved amlodipine in hypertensive patients or in patients with CAD or diabetic nephropathy. The quantitative overview by Wang et al¹⁰ was taken as the primary source.

The design and results of clinical effectiveness trials of amlodipine are summarised in Tables 1 and 2, respectively.

ALLHAT trial

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²¹ was a randomised, double-blind, active-controlled clinical trial. A total of 33,357 patients with hypertension and at least one other coronary heart disease (CHD) risk factor were randomly assigned to receive chlorthalidone 12.5–25 mg/day, amlodipine 2.5–10 mg/day, or lisinopril 10–40 mg/day for a follow-up of approximately 4–8 years.

The primary outcome was combined fatal CHD or non-fatal myocardial infarction, analysed by intention to treat. Secondary outcomes were all-cause of mortality, stroke, combined CHD (primary outcome, coronary revascularisation or angina with hospitalisation) and combined CAD (combined CHD, stroke, treated angina without hospitalisation, heart failure and peripheral arterial disease). The mean follow-up was 4.9 years. The primary outcome occurred in participants with no difference between treatments. Compared with chlorthalidone, the relative risks (RR.) were 0.98 (95% confidence interval (CI) 0.90–1.07) for amlodipine and 0.99 (95% CI 0.91–1.08) for lisinopril. Likewise, all-cause of mortality did not differ between groups. For amlodipine versus chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of heart failure (HF) with amlodipine (10.2 vs. 7.7%; RR 1.38; 95% CI 1.25–1.52). For lisinopril versus chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3 vs. 30.9%; RR 1.10; 95% CI 1.05–1.16); stroke (6.3 vs. 5.6%; RR 1.15; 95% CI 1.02–1.30); and HF (8.7 vs. 7.7%; RR 1.19; 95% CI 1.07–1.31).

ASCOT-BPLA trial

Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA)²² was a multicentre controlled randomised prospective trial which involved 19,257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors.

Patients were assigned either amlodipine 5–10 mg, adding perindopril 4–8 mg as required (amlodipine-based regimen), or atenolol 50–100 mg, adding bendroflumethiazide 1.25–2.5 mg and potassium as required (atenolol-based regimen). The primary endpoint was non-fatal myocardial infarction (including silent myocardial infarction) and fatal CHD. The study was stopped prematurely after 5.5 years' median follow-up. Although not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs. 474; unadjusted hazard ratio (HR) 0.90, 95% CI 0.79–1.02; p=0.1052), fatal and non-fatal stroke (327 vs. 422; 0.77, 0.66–0.89; p=0.0003), total cardiovascular events and procedures (1,362 vs. 1,602; 0.84, 0.78–0.90; p<0.0001), and all-cause mortality (738 vs. 820; 0.89, 0.81–0.99; p=0.025).

CAMELOT study

The Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT)⁸ study is a double-blind, randomised, multicentre, 24-month trial comparing amlodipine or enalapril with placebo in 1,991 patients with angiographically documented CAD and diastolic blood pressure <100 mmHg. Patients were randomised to receive amlodipine 10 mg, enalapril 20 mg or placebo. The primary efficacy parameter was incidence of cardiovascular events for amlodipine versus placebo. Events included cardiovascular death, non-fatal myocardial infarction, resuscitated cardiac arrest, coronary revascularisation, hospitalisation for angina pectoris, hospitalisation for congestive heart failure, fatal or non-fatal stroke or transient ischaemic attack, and new diagnosis of peripheral vascular disease. Cardiovascular events occurred in 23.1% of placebo-treated patients, in 16.6% of amlodipine-treated patients (HR 0.69; 95% CI 0.54–0.88; p=0.003), and in 20.2% of enalapril-treated patients (HR, 0.85; 95% CI 0.67–1.07; p=0.16). The primary endpoint comparison for enalapril versus amlodipine was not significant.

PREVENT trial

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicentre, randomised, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented CAD. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries. The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter. In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis. There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularisation.

IDNT trial

In the Irbesartan Diabetic Nephropathy Trial (IDNT)¹¹ 1,715 hypertensive patients with nephropathy due to type 2 diabetes were randomly assigned to treatment with irbesartan (300 mg/day), amlodipine (10 mg/day), or placebo. The target blood pressure was 135/85 mmHg or less in all groups. The groups were compared with regard to the time to the primary composite endpoint of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease (ESRD), or death from any cause. Also compared was the time to a secondary cardiovascular composite endpoint.

The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite endpoint that was 20% lower than that in the placebo group (p=0.02) and 23% lower than that in the amlodipine group (p=0.006). The risk of a doubling of the serum creatinine concentration was 33% lower in the irbesartan group than in the placebo group (p=0.003) and 37% lower in the irbesartan group than in the amlodipine group (p<0.001). Treatment with irbesartan was associated with a relative risk of ESRD that was 23% lower than that in both other groups (p=0.07 for both comparisons).

These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24% more slowly in the irbesartan group than in the placebo group (p=0.008) and 21% more slowly than in the amlodipine group (p=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite endpoint.

VALUE trial

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)¹² trial was an investigator-designed, prospective, multinational, double-blind, randomised, active-controlled, parallel-group trial where 15,245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events, were randomly assigned to treatment with valsartan (80–160 mg) or amlodipine (5–10 mg). The primary endpoint was defined as a composite of cardiac mortality and morbidity. Patients were followed up for a mean of 4.2 years.

Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period. The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1,000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1,000 patient-years; HR 1.04, 95% CI 0.94–1.15; p = 0.49).

CASE-J trial

The Candesartan Antihypertensive Survival Evaluation in Japan Trial (CASE-J)²⁴ is a prospective, multicentre, randomised, open-label, blinded assessment of endpoints in 4,728 Japanese high-risk hypertensive patients treated with either candesartan or amlodipine.

The primary endpoint was the incidence of cardiovascular events, represented as a composite of sudden death and cerebrovascular, cardiac, renal and vascular events. Patients were followed for an average of 3.2 years. Blood pressure was well controlled with both treatment-based regimens. Primary cardiovascular events occurred in 134 patients with both the candesartan- and amlodipine-based regimens. The two treatment-based regimens produced no significant differences in cardiovascular morbidity or mortality in these high-risk Japanese hypertensive patients (HR 1.01; 95% CI: 0.79–1.28; p = 0.969). In each primary endpoint category, there was no significant difference between the two treatment-based regimens.

CAPARES study

In the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES)²⁵, a prospective, double-blind design, 635 patients were randomised to 10 mg of amlodipine or placebo. Pre-treatment with the study drug started 2 weeks before percutaneous transluminal coronary angioplasty (PTCA), and continued until 4 months after PTCA. The primary angiographic endpoint was loss in minimal lumen diameter from post-PTCA to follow-up, as assessed by quantitative coronary angiography. Clinical endpoints were death, myocardial infarction, coronary artery bypass graft surgery and repeat PTCA (major adverse clinical events).

Follow-up angiography suitable for quantitative coronary angiography analysis was carried out in 37% of the patients in the amlodipine group and in 34% of patients in the placebo group (per-protocol group). The mean loss in minimal lumen diameter was 0.30 ± 0.45 mm in the amlodipine group versus 0.29 ± 0.49 mm in the placebo group (p=0.84). The need for repeat PTCA was significantly lower in the amlodipine versus the placebo group (3.1 vs. 7.3%; p=0.02, RR ratio: 0.45, 95% CI 0.22–0.91), and the composite incidence of clinical events (9.4 vs. 14.5%; p=0.049, RR ratio: 0.65, 95% CI: 0.43–0.99) within the 4 months follow-up period.

Cost effectiveness of amlodipine

The cost effectiveness of amlodipine to prevent cardiovascular mortality and morbidity has been evaluated in a number of analyses.

Generally, two approaches are taken into consideration in the cost-effectiveness analysis: a within-trial analysis and a modelling approach.

The within-trial analysis used to estimate the costs and events avoided during the trial period where local country cost is applied to resources used including: use of study drug, endpoint-related hospitalisations, non-endpoint-related hospitalisations and concomitant drugs.

The modelling approach extrapolates costs and the potential benefits of avoiding events on long-term survival and quality-adjusted survival over the lifetime of the patients²⁶.

ALLHAT trial

No cost-effectiveness data were available from this trial.

ASCOT-BPLA trial

Within-trial analysis:

Lindgren et al²⁶ conducted an economic evaluation in the UK and Sweden, the two largest contributors of patients to the trial.

In the amlodipine-based group, the cost of the study drugs was higher than with the atenolol-based strategy, but there were lower costs for all other resource categories, thus offsetting 38–50% of the drug costs during the 5.5-year trial period.

In the UK, the cost to avoid one cardiovascular event or procedure would be €18,965, while in Sweden it would be €13,210.

Long-term cost effectiveness:

To estimate long-term cost and effects, a Markov model consisting of six states (event-free, diabetes, myocardial infarction, coronary revascularisation, stroke and death) was constructed by Lindgren et al²⁶. The transition probabilities used in the model were derived from the clinical trial through survival modelling, with the exception of the risk of an event being fatal that was estimated through logistic regression. Mortality following an event was estimated based on the entire trial sample treatment arm. This means that no difference was assumed in mortality after an event for the two treatments. Any potential survival benefit was thus only caused by a difference in the risk of events. The cost of the study drug is based on the mean number of days for which each dose was prescribed during the trial period and the daily cost of the drug. Costs for events were estimated by comparing the resource consumption during the year before the event to that 1 and 2 years after it. Two measures of health outcomes were included in the model: life years gained based on the predicted survival in the two treatment groups and quality-adjusted life years gained. In the latter case, each life year is weighted according to the health status of the patient.

Modelling the lifelong predictions of costs, outcomes and cost effectiveness, Lindgren et al²⁶ found that in the UK, the cost to gain one quality-adjusted life year would be €21,875, the corresponding figures for Sweden being €16,856.

CAMELOT study

No cost-effectiveness data was available from this trial.

PREVENT trial

Within-trial analysis:

de Portu et al¹ assessed the pharmacoeconomic implications of using amlodipine besylate treatment in Italy for patients with CAD. The cost-effectiveness analysis determined the direct medical costs by referring to the combined cost of therapy- and cardiovascular-related hospitalisations using the standpoint of the principal third-party payer, the Italian National Health Service (NHS). The effects were expressed as the incidence of patients free from any clinical events.

The total cost of adding amlodipine besylate to standard care amounted to €139,050 per 1,000 patients treated for 36 months. This represents a cost of €1,780 per patient remaining free of any vascular event. Amlodipine besylate therapy can be a cost-effective strategy for CAD treatment in Italy. The economic evaluation demonstrated, first, that by reducing vascular events and the need for revascularisation procedures, savings were achieved in hospital expenditure, and, second, that such savings could significantly offset drug costs (Table 3).

Cathomas et al²⁷ analysed the cost effectiveness of amlodipine in the treatment of coronary atherosclerosis in the Swiss health system. Calculation of effectiveness showed an additional life expectancy of 0.083 years in the amlodipine cohort compared to the placebo cohort, over an observation period of 3 years. The cost effectiveness of amlodipine treatment was approximately Swiss Francs (CHF) 14,650 per life year gained. These results showed that the administration of the calcium antagonist amlodipine in CHD patients is cost effective (Table 3).

Long-term cost effectiveness:

A Markov cohort simulation model was used by Casciano et al²⁸ to estimate over time the expected outcomes and costs of hypothetical cohorts of patients with CAD treated with either amlodipine or placebo in the US.

The expected number of CVD events for amlodipine recipients was significantly lower than the number of CVD events in the placebo cohort (p<0.01). The net present value of the cost per patient for CVD treatment was estimated to be US$14,117 for amlodipine recipients and US$16,683 (1999 values, assuming a 3% discount rate) for placebo recipients over 3 years of follow-up with cost savings realised in the amlodipine cohorts after 6 months.

According to the model, amlodipine results in an expected per-patient cost savings of US$2,566 over a 3-year period, mainly due to a reduction in hospitalisations for cardiovascular-related events and procedures.

Casciano et al²⁹ quantified the impact on overall CVD treatment costs resulting from the use of amlodipine in the CAD population, again in the UK setting. A Markov cohort simulation model was developed to estimate the overall average healthcare costs of patients with CAD and to determine the cost effectiveness of the use of amlodipine as part of their treatment regimen. Outcome probabilities used in the model were based on patient-level data from the PREVENT trial. Cost estimates for inpatient and outpatient care associated with each outcome were applied to quantify the overall average healthcare cost for each arm of the study.

The hospitalisation rate per patient in the placebo cohort was 61.8% while that in the amlodipine cohort was 44.3%. This corresponds to an average cost per patient for CVD treatment of £1,858.64 for amlodipine patients and £1,800.49 for placebo patients over 3 years of follow-up. Calculations yield a cost per hospitalisation avoided of £331.67.

Doyle et al³⁰ calculated the cost effectiveness of amlodipine therapy in patients with CAD in Sweden.

They hypothesed that treatment with amlodipine would have an impact on overall CVD treatment costs, resulting in a positive cost-effectiveness profile. A Markov cohort simulation model was constructed to simulate event-related and procedure-related health economic outcomes of CHD populations on amlodipine versus those on placebo. The total number of adverse cardiovascular clinical outcomes experienced over a 3-year period was lower for patients on amlodipine than for those on placebo. The cost per patient was Swedish Kroner (SEK) 26,600 for amlodipine patients and SEK27,400 for placebo patients. The use of amlodipine resulted in improved clinical outcomes, as well as a slight savings in costs over a 3-year period (Table 3).

IDNT trial

Long-term cost effectiveness:

Using a Markov model Palmer et al³¹ calculated the cost effectiveness of treating hypertension, type 2 diabetes and nephropathy patients with irbesartan, amlodipine or control in the UK.

The treatment-specific probabilities were derived from the IDNT trial, while UK-specific end-stage renal disease (ESRD)-. related data were retrieved from published sources to reflect local management practices. Mean 10-year costs and changes in life expectancy due to ESRD delayed or avoided were calculated. The delay in the onset of ESRD with irbesartan versus amlodipine led to cost savings of £5,125 and improvements in projected discounted life expectancy of 0.07 years. The cost of treatment of ESRD was the main contributor to the total costs. The cost of trial medications had only a minor impact. These results were robust in a wide range of plausible assumptions, given that irbesartan in the UK was cost saving over a 10-year period compared to amlodipine.

Rodby et al³² estimated the cost effectiveness of irbesartan compared with placebo or amlodipine in the treatment of patients with type 2 diabetes mellitus, hypertension and overt nephropathy.

A Markov model was developed based on primary data from the IDNT trial and the US Renal Data System. Survival and costs were projected and compared for each treatment at 3-, 10- and 25-year time horizons. At 10 and 25 years, the model projected irbesartan to be both the least costly and most effective (i.e. demonstrating a survival advantage) strategy. At 25 years, the model predicted a mean gain of 7.5 months of life, with cost savings of $26,290 per patient with irbesartan versus amlodipine. At year 3, minimal differences in life expectancy were observed. The model projected a gain of 1.5 days in favour of amlodipine versus irbesartan, the gain was achieved at an added cost of $4,217 per patient (incremental cost-effectiveness ratio of $1,047,533 per life year saved).

Coyle et al³³ assessed the cost effectiveness of irbesartan and amlodipine in the treatment of Canadian patients with diabetic nephropathy and hypertension. The analysis was conducted based on a Markov model using a Monte Carlo simulation analysis to estimate the expected values for outcomes of interest. Transition probabilities were obtained from the IDNT trial and Canadian costs for health states studied were obtained from published data.

Based on the results of the simulation irbesartan was dominant over amlodipine because it both reduced costs and lead to greater life expectancy, while the incremental cost-effectiveness ratio per life year gained for amlodipine in comparison with standard care was $102,000.

VALUE trial and CASE J trial

No cost-effectiveness data was available from this trial.

CAPARES study

Within-trial analysis:

Rossetti et al¹⁸ conducted a cost-effectiveness analysis comparing amlodipine besylate added to standard care with standard care alone from the perspective of the Italian NHS. Amlodipine besylate resulted in less expensive and more effective treatment than standard care. It reduced mortality, morbidity for coronary reasons and the need of revascularisation procedures. The cost per 1,000 patients was estimated at €1,166,000 in the placebo and €950,000 in the amlodipine group, resulting in a cost saving of €216,000, that is 18.5% of the total cost of standard care. Results were sensitive to the cost of amlodipine and the cost of hospitalisations, but therapy with amlodipine acieved dominance, even in the most unfavourable hypothesis.

Thaulow et al³⁴ evaluated the health-economic benefits of using amlodipine in patients undergoing angioplasty procedures in Canada and Norway. A decision-tree model was constructed to find the total expected cost per patient for a 4-month time period following an initial angioplasty. The model used clinical outcomes from the CAPARES study and a modified Delphi study approach was used to quantify healthcare resources consumed for each clinical outcome. The total expected cost per patient using amlodipine was $6,398.30 (US$4,323) in Canada and Nok59,993.27 (US$6,846) in Norway. The total expected cost per patient not using amlodipine was $6,519.37 (US$4,405) in Canada and Nok64,292.17 (US$7,337) in Norway. The model demonstrated potential cost savings over a 4-month follow up period resulting from the improved clinical outcomes for patients using amlodipine with PTCA of $121,071 (US$81,844) per 1,000 patients in Canada and Nok4,298,899 (US$490,074) per 1,000 patients in Norway (Table 4).

Doyle et al³⁵ determined and compared the total expected costs in the UK for patients using amlodipine versus those on placebo following an initial angioplasty. They constructed a decision-tree model to estimate these total expected costs. Clinical outcomes for the model, including myocardial infarction, repeat PTCA, coronary artery bypass grafting and all-cause mortality, were obtained from the CAPARES study.

Resource usage and economic data were produced through the use of a modified Delphi panel and various economic literature and databases. They found that the adjunctive use of amlodipine with PTCA decreased the rate of all adverse clinical outcomes by 9.4%. This improvement in clinical outcome led to a decrease in overall 4-month costs per patient using amlodipine of £204. The total expected cost per patient using amlodipine was £3,833 and the total expected cost per patient not using amlodipine was £4,037 (Table 4).

Discussion

The main finding of the overview by Wang et al¹⁰ was that calcium channel blockade through the use of amlodipine substantially reduced the risk of stroke and myocardial infarction. The benefit of initial treatment with this drug versus other antihypertensive drugs could be largely, though not entirely, explained by blood pressure differences between randomised groups of trial participants.

ARbs, when contrasted with amlodipine, were less effective in lowering blood pressure and also demonstrated inferiority for the prevention of stroke and myocardial infarction.

The findings of Wang et al on amlodipine versus diuretics, β-blockers, or ACE inhibitors are in keeping with the results of previous meta-analyses^6,7,14,15,36, which showed that calcium channel blockade in general provides more protection against stroke^6,7,14,15 and that amlodipine in particular provides similar protection against myocardial infarction³⁶. Calcium channel blockade prevents intima–media thickening³⁷ and this might contribute to the observed 11% of blood pressure-independent benefit of amlodipine on stroke.

The clinical effectiveness of amlodipine has been well documented in a number of randomised clinical trials even if, given the inclusion and exclusion criteria, data from clinical trials might not be generalisable to all the CAD patients.

Knowledge not only about clinical but also about economic consequences deriving from these therapies will presumably be useful to healthcare providers and decision makers who are committed to recognising and applying efficient interventions in CAD care.

CAD, in fact, is a potentially life-threatening condition that requires continuous long-term medical management, and often necessitates high-cost revascularisation procedures and repeated hospitalisation²⁸. Upon diagnosis it is critical that measures are taken to impede the progression of the disease. A recent review by Brown and colleagues³⁸ demonstrated the importance of disease prevention strategies in adults with CAD most of which were non-surgical. Ideally, non-invasive treatment approaches should minimise future CVD-related events and the need for invasive surgery²⁹.

Considering the limitations of comparing economic evaluations in different populations, the results of the available pharmacoeconomic analyses demonstrated that the use of amlodipine resulted in fewer hospitalisations and the need for fewer invasive surgical procedures in the short and long term at a modest cost increase.

Amlodipine in fact is not only cost effective, but predicted to be cost saving when compared with usual care, warranting its consideration as an agent of choice in patients with CAD. Of note is the fact that the pharmacoeconomic analyses reviewed in this study did not consider amlodipine as an off-patent medication. At the present time amlodipine is a generic medicine, and if pharmacoeconomic analyses are performed using current amlodipine prices, the results would prove it to be even more cost effective and cost saving. Unfortunately, pharmacoeconomic evidence from the ALLHAT study, the largest trial evaluating amlodipine efficacy, is not available.

An additional limitation is that only direct costs were considered while indirect costs attributable to time or productivity losses were not included in this economic analysis. Therefore it is likely that the inclusion of indirect costs would have increased the economic benefit derived from the use of amlodipine besylate.

Ideally, non-invasive treatment approaches should eliminate future CVD-related events and the need for invasive surgery; however, no definitive treatment choice exists to accomplish this objective²⁸.

Consequently, payers and providers of healthcare are continually forced to make clinical and economic decisions regarding the use of treatments. Hence, in the ongoing effort to impede the continued exponential growth of healthcare budgets, we need to identify the most appropriate medical treatments, not only from the standpoint of health outcomes, but from a purely economic perspective as well²⁸.

These decisions must be based on objective evaluations of available data such as the analysis presented here.

Table 1. Summary of amlodipine clinical effectiveness trials: design and endpoints.

Study	Population (N)	Design
ALLHAT^21	Patients with hypertension and at least one other CHD risk factor (33,357)	Chlorthalidone (12.5–25 mg) vs. amlodipine (2.5–10 mg) or lisinopril (10–40 mg) for mean 4.9 years
ASCOT-BPLA^22	Patients with hypertension and three cardiovascular risk factors (19,257)	Amlodipine (5–10 mg) vs. atenolol (50–100 mg) for median 5.5 years
CAMELOT^8	Patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mmHg (1,991)	Amlodipine (5–10 mg) or enalapril (10–20 mg) vs. placebo for 2 years
PREVENT^23	Patients with angiographically documented CAD (825)	Amlodipine (5–10 mg) vs. placebo for mean 3 years
IDNT^11	Hypertensive patients with nephropathy due to type 2 diabetes (1,715)	Amlodipine (2.5–10 mg) or irbesartan (75–300 mg) vs. placebo for mean 2.6 years
VALUE^12	Patients with treated or untreated hypertension and high risk of cardiac events (15,245)	Amlodipine (5–10 mg) vs. valsartan (80–160 mg) for mean 4.2 years
CASE-J^24	High-risk hypertensive patients (4,728)	Amlodipine (2.5–10 mg) vs. candesartan (4–10 mg) for mean 3.2 years
CAPARES^25	Patients suitable for elective balloon angioplasty of one or more of the major coronary arteries (635)	Amlodipine (5–10 mg) vs. placebo for median 4 months

CHD, coronary heart disease; CAD, coronary artery disease.

Table 2. Summary of amlodipine clinical effectiveness trials: results.

Study	Endpoint	Results
		Amlodipine (%)	Other drug (%)	HR/RR (95% CI)	p-value
ALLHAT^21	Coronary death and MI (mean 4.9 years)	11.3	11.5	0.98 (0.90–1.07)	0.65
ASCOT-BPLA^22	Coronary death and MI (median 5.5 years)	5	5	0.90 (0.79–1.02)	0.1052
CAMELOT^8	CV events (CV death, non-fatal MI, RCA, AP, CR, HF, stroke or TIA, PAD) (2 years)	16.6	20.2	0.81 (0.63–1.04)	0.10
IDNT^11	All-cause death and ESRD and DBSC (mean 2.6 years)	41.1	32.6	0.77 (0.63–0.93)	0.006
VALUE^12	Cardiac mortality and morbidity (mean 4.2 years)	10.4	10.6	1.04 (0.94–1.15)	0.49
CASE-J^24	CV events (CV death, MI, AP, HF, CBV, VE, ESRD) (mean 3.2 years)	5.7	5.7	1.01 (0.79–1.28)	0.969
		Amlodipine (%)	Placebo (%)
CAMELOT^8	Cardiovascular events (CV death, non-fatal MI, RCA, AP, CR, HF, stroke or TIA, PAD) (2 years)	16.6	23.1	0.69 (0.54–0.88)	0.003
PREVENT^23	Any major/documented vascular events or procedures (mean 3 years)	20.6	28.4	0.69 (0.52–0.92)	0.01
IDNT^11	All cause of death and ESRD and DBSC (mean 2.6 years)	41.1	39.0	1.04 (0.86–1.25)	0.69
CAPARES^25	Death, MI, CABG, repeat PTCA (4 months)	9.4	14.5	0.65 (0.43–0.99)	0.049

HR, hazard ratio; RR, relative risk; CI, confidence interval; MI, myocardial infarction; CV, cardiovascular; RCA, resuscitated cardiac arrest; AP, angina pectoris; CR, coronary revascularisation; HF, heart failure; TIA, transient ischaemic attack; PAD, peripheral arterial disease; ESRD, end-stage renal disease; DBSC, doubling of baseline serum creatinine concentration; CABG, coronary artery bypass graft surgery; PTCA, percutaneous transluminal coronary angioplasty; CBV, cerebrovascular events including stroke and transient ischaemic attack; VE vascular events.

Table 3. Cost effectiveness of amlodipine based on PREVENT trial.

Study	Country	Cost per CV event avoided
de Portu et al (1)	Italy	€1,780
Casciano et al (28)	US	Dominant
Caciano et al (29)	UK	£331.67
Doyle et al (30)	Sweden	Dominant
		Cost per life year gained
Cathomas et al (27)	Swiss	CHF14,650

CV, cardiovascular.

Table 4. Cost effectiveness of amlodipine based on CAPARES trial.

Study	Country	Cost per CV event avoided
Rossetti et al (18)	Italy	Dominant
Thaulow et al (34)	Canada	Dominant
Thaulow et al (34)	Norway	Dominant
Doyle et al (35)	UK	Dominant

CV, cardiovascular.

Acknowledgements

Declaration of interest: The authors have declared no conflicts of interest and have received no payment in the preparation of this manuscript.