Amlodipine Response Rates in Trials and With Telmisartan

What a Response Rate Actually Measures

The published percentages are not interchangeable, because each trial set its own bar for a response.

In the Korean study of telmisartan plus S-amlodipine, the systolic criterion was a pressure below 140 mm Hg or a fall of at least 20 mm Hg; the diastolic criterion was a pressure below 90 mm Hg or a fall of at least 10 mm Hg [4]. A telmisartan combination trial required both a 20 mm Hg systolic and a 10 mm Hg diastolic reduction [1]. The fimasartan/amlodipine trial counted a sitting systolic pressure below 140 mm Hg or a fall of 20 mm Hg [6]. The 1999 amlodipine titration study used only a diastolic pressure of 90 mm Hg or less [3]. The abstract of the 1,051-patient amlodipine trial does not give its response definition [2].

Amlodipine Response Rates in Trials

The largest of these trials enrolled 1,051 adults with mild to moderate hypertension at 22 centers and randomized them open-label to three treatments for 8 weeks [2]. Response rates were 72.4% on L-amlodipine besylate 2.5 mg, 85.6% on L-amlodipine besylate 5 mg and 76.2% on amlodipine maleate 5 mg. The high-dose L-amlodipine arm differed from both other arms (P<0.01), the low-dose L-amlodipine and amlodipine maleate arms did not differ (P=0.28), and adverse event rates were 4.3%, 4.6% and 5.1% (P=0.84) [2].

The trial did not test Norvasc or generic amlodipine besylate: its arms were amlodipine maleate and two doses of L-amlodipine besylate. The 76.2% figure therefore describes amlodipine maleate 5 mg, not the amlodipine besylate in Norvasc, and the two L-amlodipine besylate arms gave 72.4% and 85.6%.

A smaller trial randomized 115 patients at 10 centers to 5 mg once daily throughout or to 5 mg with the option of raising the dose to 10 mg if diastolic pressure exceeded 90 mm Hg [3]. The dose was raised in 40% of the flexible-dose group, 20 of 50 patients. Diastolic and systolic pressure fell steadily until the end of week 6 in both groups with no significant difference between them, and 84% of both groups finished with a diastolic pressure of 90 mm Hg or less [3]. The authors concluded that an early dose increase offered no advantage and that an increase should not be considered until after six weeks at 5 mg once daily [3].

The amlodipine besylate tablet label describes a hypertension program of 15 double-blind, placebo-controlled randomized trials with 800 patients on amlodipine and 538 on placebo, and reports average placebo-corrected reductions at 24 hours after a dose of about 12/6 mm Hg standing and 13/7 mm Hg supine rather than a responder rate [5].

Telmisartan vs Amlodipine: What the Comparison Trials Show

The comparison data come from trials that pair the two drugs, or that pair telmisartan with and without amlodipine.

In 108 patients whose pressure was still uncontrolled after 4 weeks of telmisartan 20 mg, 8 weeks of telmisartan 20 mg with S-amlodipine 2.5 mg lowered mean sitting systolic pressure by 16.97 mm Hg against 7.42 mm Hg with telmisartan 40 mg alone (P<0.001) [1]. Diastolic reductions were 7.98 and 4.01 mm Hg (P=0.006), and the control rate was 53.70% vs 29.63% (P=0.010) [1]. On that trial's stricter response definition, requiring both a 20 mm Hg systolic and a 10 mm Hg diastolic fall, the rates were 12.96% vs 5.56% and did not differ significantly (P=0.182); treatment-emergent adverse events were 9.26% vs 20.37% (P=0.104), most of them mild [1].

A 374-patient phase 3 trial compared telmisartan 80/amlodipine 5/chlorthalidone 25 mg with telmisartan 80/amlodipine 5 mg over 8 weeks from a baseline of 149.9/88.5 mm Hg [7]. Mean sitting systolic pressure fell 19.1 mm Hg on the triple combination and 11.4 mm Hg on the dual (P<0.0001); target attainment was 53.8% vs 37.8% (P=0.0017) and the responder rate 54.8% vs 35.6% (P=0.0001) [7]. No serious adverse event occurred and nobody discontinued for an adverse event; within the triple-therapy group, women and patients aged 65 or older reached target more often than younger men (61.4% vs 46.8%, P=0.042) [7].

The largest dataset is a Korean surveillance study of 44,715 adults prescribed telmisartan plus S-amlodipine, 41,579 of whom entered the efficacy analysis and were followed for 3 to 6 months [4]. Systolic pressure fell from 143.1 to 129.6 mm Hg and diastolic from 88.1 to 80.1 mm Hg (difference -13.5/-7.9, P<0.0001) [4]. Target attainment below 140/90 mm Hg was 74.6% (95% CI 74.2 to 75.0) and the response rate 94.5% (95% CI 94.3 to 94.7) [4]. Adverse events were reported in 1.81% of patients and adverse drug reactions in 0.79%; dizziness (0.30%) and headache (0.18%) were the most common adverse events, and total edema was 0.08% and leg edema 0.06% [4].

A network meta-analysis pooled 32 randomized trials with 16,273 patients whose hypertension was uncontrolled and compared 11 single-pill combinations [8]. By SUCRA ranking, telmisartan/amlodipine may rank first for blood pressure control rate (SUCRA 83.5%), irbesartan/amlodipine may rank first for systolic reduction (SUCRA 92.2%), and amlodipine/losartan may rank first for diastolic reduction (SUCRA 95.1%) and diastolic response rate (SUCRA 84.5%) [8]. The authors concluded that single-pill combinations outperform monotherapy and that ARB/CCB combinations hold an advantage on these measures, and cautioned that some drugs rested on few trials [8].

Individual Variation in Response

A crossover study of 56 untreated young hypertensive patients, mean pressure 161/98 mm Hg, rotated four drug classes a month at a time — an ACE inhibitor, a beta-blocker, a calcium channel blocker and a diuretic — with 36 patients completing all four cycles [9]. Of the 41 patients who reached 140/90 mm Hg or less at some point, 20 failed to reach it on their first drug; rotation raised monotherapy success from 22 of 56 (39%) to 41 of 56 (73%, p=0.0001) [9]. Responses to the ACE inhibitor and beta-blocker correlated (r=0.5, p<0.01), as did responses to the calcium channel blocker and diuretic (r=0.6, p<0.001), and the ACE inhibitor/beta-blocker responses averaged at least 50% larger than the calcium channel blocker/diuretic responses [9].

For amlodipine itself, the label reports similar blood pressure effects in black and in white patients, and a larger systolic effect in older patients, perhaps because of their greater baseline systolic pressure [5].

Side Effects

The amlodipine besylate tablet label calls edema the most common adverse reaction and shows it rising with dose: 1.8% at 2.5 mg, 3.0% at 5 mg and 10.8% at 10 mg, against 0.6% on placebo [5]. Dizziness came in at 1.1%, 3.4% and 3.4% vs 1.5%; flushing at 0.7%, 1.4% and 2.6% vs 0.0%; palpitation at 0.7%, 1.4% and 4.5% vs 0.6% [5]. Edema was reported by 14.6% of women vs 5.1% on placebo and by 5.6% of men vs 1.4%, and flushing by 4.5% vs 0.9% of women and 1.5% vs 0.3% of men [5].

Reactions not clearly dose related included fatigue (4.5% vs 2.8%), nausea (2.9% vs 1.9%), abdominal pain (1.6% vs 0.3%) and somnolence (1.4% vs 0.6%) [5]. Discontinuation for adverse reactions was required in about 1.5% of patients on amlodipine against about 1% on placebo [5].

Gingival hyperplasia and angioedema sit among events reported in under 1% but over 0.1% of patients in the label's trials, where a causal relationship is uncertain; weight gain and weight decrease are listed in the same group [5].

The 44,715-patient Korean cohort reported total edema of 0.08% and leg edema of 0.06% on telmisartan plus S-amlodipine [4]. Those figures come from a surveillance study of a combination product and are not directly comparable with the label's trial rates.

Dosing, Titration and Interactions

The labeled adult starting dose is 5 mg once daily with a maximum of 10 mg once daily; small, fragile or elderly patients and patients with hepatic insufficiency may start at 2.5 mg, and the label advises waiting 7 to 14 days between titration steps unless faster titration is clinically warranted [5]. In severe hepatic impairment the label says to titrate slowly, noting a plasma elimination half-life of 56 hours in impaired hepatic function [5].

The label's drug interaction section says that moderate and strong CYP3A inhibitors increase exposure to amlodipine and may require a dose reduction, with monitoring for symptoms of hypotension and edema [5]. It states that no quantitative information is available on CYP3A inducers and that blood pressure should be closely monitored when amlodipine is given with them [5]. The label also limits simvastatin to 20 mg daily in patients taking amlodipine [5].

In an Ontario cohort of adults taking a calcium channel blocker, more than half of them amlodipine, a new clarithromycin prescription compared with a new azithromycin prescription was associated within 30 days with hospitalization for acute kidney injury in 0.44% vs 0.22% (OR 1.98, 95% CI 1.68 to 2.34), hospitalization for hypotension in 0.12% vs 0.07% (OR 1.60) and all-cause mortality of 1.02% vs 0.59% (OR 1.74) [10].

Grapefruit juice has been studied directly with amlodipine. In 12 healthy men given a single 5 mg dose with 250 mL of grapefruit juice or water, peak plasma concentration reached 115% and exposure over 72 hours 116% of the water values, with no significant difference in blood pressure or heart rate [11]. In 20 healthy men taking juice or water once daily for 9 days with a single 10 mg dose, oral availability was 88% with juice and 81% with water, and exposure, peak concentration and clearance were not markedly changed [12].