Amlodipine Cardiovascular Impact: Long-Term Evidence, Trials, and Clinical Guidance

What amlodipine does, in one paragraph

Amlodipine inhibits calcium influx across cell membranes, with a greater effect on vascular smooth muscle than on cardiac muscle, and acts as a peripheral arterial vasodilator that lowers peripheral vascular resistance and blood pressure [1]. Onset is gradual because its binding to the calcium channel has a slow association and dissociation rate, and serum calcium is not affected [1].

What the Norvasc label covers

The labeled indications are hypertension, chronic stable angina, vasospastic (Prinzmetal) angina, and, in patients with angiographically documented coronary artery disease who do not have heart failure and do not have an ejection fraction below 40%, reduction in the risk of hospitalization for angina and of coronary revascularization [1].

On why blood pressure drugs help, the label says lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions, and that it can be concluded that blood pressure reduction, and not some other pharmacologic property of the drugs, is largely responsible for those benefits [1].

Adult hypertension dosing starts at 5 mg once daily with a maximum of 10 mg once daily [1]. Small, frail or elderly patients, patients with hepatic insufficiency, and those adding amlodipine to other blood pressure medicines may start at 2.5 mg once daily [1]. The label advises 7 to 14 days between titration steps unless faster titration is warranted [1]. For angina and for coronary artery disease the range is 5 to 10 mg once daily, and most patients in those studies needed 10 mg [1].

CAMELOT: coronary disease with near-normal blood pressure

CAMELOT randomized 1,991 patients with angiographically documented coronary artery disease (more than 20% stenosis) and diastolic blood pressure below 100 mmHg to amlodipine 10 mg, enalapril 20 mg, or placebo for 24 months; baseline blood pressure averaged 129/78 mmHg [2]. The primary cardiovascular composite occurred in 110 patients on amlodipine (16.6%) versus 151 on placebo (23.1%), hazard ratio 0.69 (95% CI 0.54-0.88), P=0.003 [2]. Enalapril reached 136 events (20.2%) and did not separate from placebo (HR 0.85) [2]. Blood pressure fell 4.8/2.5 mmHg on amlodipine and 4.9/2.4 mmHg on enalapril [2].

Most of the amlodipine advantage came from fewer hospitalizations for angina (51 versus 84) and fewer revascularizations (78 versus 103) [2]. A 274-patient intravascular ultrasound substudy measured change in percent atheroma volume as an additional endpoint [2].

ASCOT-BPLA: 19,257 patients over 5.5 years

The trial enrolled patients aged 40 to 79 with hypertension and at least three other cardiovascular risk factors, assigned to amlodipine 5 to 10 mg adding perindopril 4 to 8 mg as required (n=9,639) or atenolol 50 to 100 mg adding bendroflumethiazide and potassium as required (n=9,618) [3]. It was stopped prematurely after a median follow-up of 5.5 years [3].

The primary endpoint of nonfatal myocardial infarction plus fatal coronary heart disease was not significantly reduced: 429 versus 474 events, unadjusted HR 0.90 (95% CI 0.79-1.02), P=0.1052 [3]. Other outcomes were: stroke 327 versus 422, HR 0.77 (0.66-0.89), P=0.0003; total cardiovascular events and procedures 1,362 versus 1,602, HR 0.84, P<0.0001; all-cause mortality 738 versus 820, HR 0.89 (0.81-0.99), P=0.025; and new diabetes 567 versus 799, HR 0.70, P<0.0001 [3]. The investigators concluded that the amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen, and that these effects might not be entirely explained by better blood pressure control [3].

VALUE: amlodipine versus valsartan

VALUE randomized 15,245 patients aged 50 or older at high cardiac risk to valsartan-based or amlodipine-based therapy for a mean of 4.2 years [4]. Blood pressure fell more on amlodipine: 4.0/2.1 mmHg lower after 1 month and 1.5/1.3 mmHg lower after 1 year (P<0.001) [4]. In VALUE, the primary outcome occurred in 810 patients on valsartan (10.6%) and 789 on amlodipine (10.4%). The hazard ratio for valsartan versus amlodipine was 1.04 (95% CI 0.94-1.15; P=0.49) [4]. The investigators stated that the main outcome of cardiac disease did not differ between groups and that unequal blood pressure reductions might account for differences in cause-specific outcomes [4].

ACCOMPLISH: amlodipine in a combination pill

ACCOMPLISH assigned 11,506 high-risk hypertensive patients to benazepril plus amlodipine or benazepril plus hydrochlorothiazide, and was terminated early at a mean follow-up of 36 months [5]. The primary composite occurred in 552 patients (9.6%) on benazepril-amlodipine and 679 (11.8%) on benazepril-hydrochlorothiazide, an absolute reduction of 2.2% and a relative reduction of 19.6% (HR 0.80, 95% CI 0.72-0.90, P<0.001) [5]. The secondary endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke had an HR of 0.79 (0.67-0.92), P=0.002, at achieved pressures of 131.6/73.3 versus 132.5/74.4 mmHg [5]. This trial tested a two-drug strategy, not amlodipine alone.

Does the benefit come from more than blood pressure?

The CAFE substudy of ASCOT recorded radial artery applanation tonometry in 2,199 patients across five centers for up to 4 years [6]. Brachial systolic pressures were nearly identical between arms (difference 0.7 mmHg, 95% CI -0.4 to 1.7, P=0.2), but central aortic systolic pressure was 4.3 mmHg lower and central aortic pulse pressure 3.0 mmHg lower on the amlodipine regimen (P<0.0001 for both) [6]. Central pulse pressure was associated with a post hoc composite of cardiovascular events and renal impairment, and the authors proposed the difference in central aortic pressure as a possible mechanism behind the differing outcomes between the two arms [6].

Long-term safety

Norvasc has no boxed warning, and the only labeled contraindication is known sensitivity to amlodipine [1]. In placebo-controlled trials of up to 10 mg (N=1,730 versus 1,250 on placebo), about 1.5% of amlodipine patients stopped for adverse reactions versus about 1% on placebo [1].

Edema is the characteristic effect and is dose related: 1.8% at 2.5 mg, 3.0% at 5 mg and 10.8% at 10 mg versus 0.6% on placebo [1]. Palpitation (0.7%, 1.4% and 4.5% at 2.5, 5 and 10 mg versus 0.6%) and flushing (0.7%, 1.4% and 2.6% versus 0.0%) also rose with dose, while dizziness was 3.4% at both 5 and 10 mg versus 1.5% on placebo [1]. Edema was more frequent in women (14.6% versus 5.1% on placebo) than in men (5.6% versus 1.4%) [1]. Therapy has not been associated with clinically relevant changes in potassium, glucose, lipids, uric acid, BUN or creatinine [1].

The label warns that symptomatic hypotension is possible, particularly in severe aortic stenosis, though acute hypotension is unlikely; that worsening angina and acute myocardial infarction can develop after starting or increasing the dose, particularly in severe obstructive coronary artery disease; and that the plasma half-life is 56 hours in impaired hepatic function, so titration should be slow in severe hepatic impairment [1].

Heart failure

The labeled coronary artery disease indication excludes patients with heart failure or an ejection fraction below 40% [1]. In PRAISE, 1,153 patients with severe chronic heart failure and ejection fractions below 30% were randomized to amlodipine or placebo for 6 to 33 months: the primary endpoint was reached in 42% of the placebo group and 39% of the amlodipine group, a 9% reduction in combined risk (P=0.31), and death occurred in 38% versus 33%, a 16% reduction (P=0.07) [7]. Among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk by 31% (P=0.04) and the risk of death by 46% (P<0.001) [7]. The investigators concluded that amlodipine did not increase cardiovascular morbidity or mortality and that the survival possibility in nonischemic dilated cardiomyopathy required further study [7].

Interactions that matter over years of use

Moderate and strong CYP3A inhibitors raise amlodipine exposure and may require dose reduction, with monitoring for hypotension and edema [1]. Diltiazem 180 mg daily with amlodipine 5 mg in elderly hypertensive patients raised amlodipine exposure by 60% [1]. In a population-based Ontario cohort of adults with a mean age of 76 taking a calcium channel blocker (amlodipine in more than half), those newly given clarithromycin (n=96,226) had more events within 30 days than those given azithromycin (n=94,083): hospitalization with acute kidney injury 0.44% versus 0.22% (OR 1.98, 95% CI 1.68-2.34), hospitalization with hypotension 0.12% versus 0.07% (OR 1.60), and death 1.02% versus 0.59% (OR 1.74) [8]. The cohort covered several calcium channel blockers, not amlodipine alone.

Amlodipine is a weak CYP3A inhibitor [1]. Multiple doses of amlodipine 10 mg with simvastatin 80 mg raised simvastatin exposure by 77%, and the label limits simvastatin to 20 mg daily in patients taking amlodipine; the combination is allowed within that cap [1][9]. Amlodipine does not affect exposure to atorvastatin, digoxin or ethanol, or the warfarin prothrombin response time [1]. It may raise cyclosporine trough levels by about 40% (N=11) and tacrolimus exposure 2.5- to 4-fold in CYP3A5 expressers (N=9); the label recommends frequent monitoring of trough levels and dose adjustment when appropriate [1]. Grapefruit juice has no impact on amlodipine exposure according to the label [1]; one crossover study in 12 men found peak concentration at 115% and AUC at 116% of water values after a single 250 mL glass, and a four-way crossover in 20 men found no marked pharmacokinetic change with 9 days of daily juice [10][11].

What these trials do not settle

The four outcome trials above ran 24 months to 5.5 years in people selected for coronary disease or high cardiovascular risk, and each compared amlodipine with a specific alternative or with placebo rather than with every other strategy [2][3][4][5]. They do not establish that amlodipine is superior to another drug class at the same achieved blood pressure; VALUE found no difference in its cardiac primary composite against valsartan, and the central-pressure explanation offered for ASCOT remains a hypothesis [4][6].