Verapamil vs. DiltiazemReplacement to the List

Peer Feedback:“Verapamil is more constipating and is a stronger negative inotrope so more caution required in the context of concern for heart failure (e.g. with concomitant atrial fibrillation)”

"(diltiazem has a) better side effect profile compared to verapamil which can be removed"

Literature Review Question:What are the side effect profiles of calcium channel blockers?What is the efficacy of various calcium channel blockers?

Literature Search:eCPS – Supraventricular Tachycardia, Hypertension, Stable AnginaPubmed – “calcium channel blocker AND (hypertension OR angina) AND (verapamil OR diltiazem OR nifedipine OR amlodipine) AND (efficacy OR safety)”; “diltiazem AND verapamil AND (safety or tolerability OR side effect)”; “nifedipine AND amlodipine AND review/meta-analysis”

Atrial fibrillation (acute onset) BMJ (2014)

One systematic review concluded that the available evidence suggests that calcium channel blockers, such as diltiazem and verapamil, reduce ventricular rate in acute- or recent-onset atrial fibrillation. However, these drugs are probably no better than placebo for restoring sinus rhythm. We found no studies of the effect of rate-limiting calcium channel blockers on exercise tolerance in people with acute- or recent-onset atrial fibrillation, but studies in people with chronic atrial fibrillation found improved exercise tolerance. [27]

We found one systematic review (search date 1998) [52] and two additional RCTs [59] [60] comparing digoxin with placebo in people with chronic atrial fibrillation, which found that control of the ventricular rate during exercise was poor unless a beta-blocker or rate-limiting calcium channel blocker (verapamil or diltiazem) was used in combination. One systematic review on atrial fibrillation concluded that intravenous beta-blockers or rate-limiting calcium channel blockers should be used for people requiring urgent pharmacological rate control. Where these drugs are ineffective or contraindicated, amiodarone should be used. [27] It is not clear whether these results can be extrapolated to people with acute atrial fibrillation.

Beta-blockers or non-dihydropyridine calcium channel antagonists are recommended as first-line treatment for rate control of atrial fibrillation. [2] There is no RCT to compare the effects of metoprolol or other drugs within the same class versus placebo in recent-onset atrial fibrillation. By extrapolating data from persistent and chronic atrial fibrillation, beta-blockers, as a class, seem to be a safe and effective treatment for rate control. Beta-blockers may exacerbate heart failure and hypotension in acute atrial fibrillation and can precipitate bronchospasm. [63] Co-administration of beta-blockers and rate-limiting calcium channel blockers (diltiazem and verapamil) may increase the risk of asystole and sinus arrest. [64] [65] [66]

Verapamil versus diltiazem: We found one small, double-blind, crossover RCT (17 men, 5 with acute atrial fibrillation, 10 with atrial flutter, and 2 with a combination of atrial fibrillation and atrial flutter; ventricular rate at least 120 beats/minute, systolic blood pressure at least 100 mmHg), which compared iv verapamil versus iv diltiazem and found no difference in rate control or

measures of systolic function. [69] In the RCT, three people who received verapamil developed symptomatic hypotension and were withdrawn from the study before crossover. [69] Two people recovered, but the episode in the third person was considered life-threatening. In people with Wolff-Parkinson-White syndrome, verapamil may increase ventricular rate, and can cause ventricular arrhythmias. [57] Rate-limiting calcium channel blockers may exacerbate heart failure and hypotension.

Gregory YH Lip and Stavros Apostolakis, “Atrial fibrillation (acute onset).” BMJ. 2014

Calcium Channel Blockers (2011)

Nondihydropyridine calcium channel blockers are more negatively chronotropic and inotropic than the dihydropyridine subclass, which is important for patients with cardiac dysrhythmias or who need b-blockers. Extensive experience in comparative randomized trials indicates that an initial calcium antagonist can prevent all major types of cardiovascular disease, except heart failure (for which a diuretic is superior). Initial dihydropyridine calcium channel blockers have not reduced the rate of progression of renal disease as well as inhibitors of the renin-angiotensin system, although members of the nondihydropyridine subclass can reduce albuminuria.High doses of dihydropyridine calcium channel blockers often cause edema, headache, flushing and tachycardia; high doses of verapamil can cause constipation.Common adverse effects of CCBs include edema, flushing, headache, dizziness, constipation (particularly with high-dose verapamil), nausea, rash, and drowsiness. CCBs have many important drug interactions. Verapamil and diltiazem increase digoxin levels. Verapamil, diltiazem, and nicardipine increase plasma levels and decrease the dosing requirement for cyclosporine. Verapamil and diltiazem are metabolized by CYP3A4, therefore inducers (eg, rifampin) and inhibitors (eg, erythromycin, cimetidine) are likely to result in decreased and increased plasma levels of these two CCBs, respectively. Concomitantly administered grapefruit juice elevates the oral bioavailability of felodipine, nifedipine, nicardipine, nisoldipine, and verapamil. Because of their shared negative effects on heart rate and myocardial contractility, b-blockers and verapamil are not used simultaneously.

Elliott, William J., and C. Venkata S. Ram. "Calcium channel blockers." The Journal of Clinical Hypertension 13.9 (2011): 687-689.

Calcium Antagonists (2004)

Unlike the other calcium channel blockers, verapamil can have clinically significant bronchodilator effects, but it is also the most likely to produce untoward constipation.

Grossman, Ehud, and Franz H. Messerli. "Calcium antagonists." Progress in cardiovascular diseases 47.1 (2004): 34-57.

In Vitro Comparison (1996)

Inotropic effect

Nifedipine, verapamil and diltiazem produced concentration-dependent negative inotropic effects on isolated guinea-pig left atrial preparations (Fig. 2). The potency order was nifedipine>verapamil>diltiazem, EC30values being 4.94 × 10 8M, 1.49 x 10 7M and 8.03 × 10-7M, respectively (Table 1). Efonidipine, even at 1 ~tM produced no inotropic effect: I0 ~tM efonidipine decreased the contractile force by about 20% (Fig. 2; Table 1)

Tanaka, Hikaru, et al. "Myocardial and vascular effects of efonidipine in vitro as compared with nifedipine, verapamil and diltiazem." General Pharmacology: The Vascular System 27.3 (1996): 451-454.

CCAs Side-effects (1988)

Verapamil Side Effects

Relatively minor side effects are those of vasodilation--headaches and dizziness, with occasional palpitations and hypotension [2]. Ankle edema may also result (Table IV-2). The side effect causing trouble, especially in elderly patients, is constipation. Straining at stool can in turn cause cardiovascular problems such as syncope. The incidence of constipation occurs in 25% to 40% of patients [2, 3]. With a higher mean dose (416 mg daily), constipation occurred in 10 of 16 patients, i.e., 63% [4]. The minor side effects of verapamil, apart from constipation, are somewhat less than those of nifedipine when both are used in doses equipotent for chronic stable angina [5] or hypertension [6].

Severe side effects with verapamil were initially stressed by reports of fatality when intravenous verapamil was abruptly given to isolated patients with pre-existing atrioventricular AV inhibition by disease or ~-adrenergic blockade [7]. In addition to individual case reports of fatalities, largely resulting from asystole, there have been several "near-misses" [3]. The thrust of Fleckenstein's [8] original experiments in defining myocardial depression as a basic property of calcium channel antagonists led to the view that calcium channel antagonists must be negative inotropic agents. Logically, the combination of therapy by calcium channel antagonists and ~-blockade was feared [9]. It is now becoming apparent that calcium channel antagonists, when correctly used, seldom induce a serious negative inotropic state [10]. Furthermore, careful patient selection has diminished the possibility of severe side effects. In the case of verapamil, sick sinus syndrome, pre-existing AV nodal disease, excess therapy with 13-adrenergic blockade or digitalis or quinidine, and myocardial depression, are all still contraindications which especially apply in the intravenous therapy of supraventricular tachycardias [3, 11, 12]. In the rarer type of Wolff-Parkinson-White syndrome with anterograde (= antegrade) conduction through the bypass tract, the risk of verapamil is that atrial fibrillation can be too rapidly conducted to the ventricles with fear of ventricular fibrillation. Nonetheless, verapamil can be safely used in the vast majority of patients with supraventricular tachycardias and narrow QRS complexes.

Diltiazem Side Effects

Subjective or relatively minor side effects. When diltiazem is given for angina, the incidence of side effects seems to be remarkably low [2]. In the United States, the package insert claims that side effects of oral therapy are similar to those of placebo, but lists nausea (3%), pedal edema (2%), headache (2%), and heart block (0.4%), and in two trials diltiazem for stable angina was "remarkably free of adverse effects" in doses of 240 mg daily [33] and all doses (up to 360 mg daily) were "extremely well tolerated" [34]. The true incidence of side effects will clearly depend on the severity of underlying myocardial or conduction system disease, the skill of the prescribing physician, and the dose of diltiazem.

Potentially serious nodal and myocardial side effects of diltiazem. Because experience with the intravenous form has been limited to carefully controlled studies, the type of serious negative chronotropic or inotropic side effect previously found with verapamil has not yet been reported. Furthermore, the general impression (supported by animal data; see Table I-6) is that diltiazem is less negatively inotropic than verapamil. However, few or no careful comparative clinical studies with these end points appear to exist. Even the oral drug can inhibit AV and/or sinus nodal tissue with AV dissociation and severe sinus bradycardia, as shown by the three patients with angina or coronary artery spasm reported by Ishikawa et al. [40]. Such side effects can especially be expected when the patients selected for diltiazem therapy have pre-existing sinus or AV nodal disease or when there is co-therapy with ~- blockade or during digitalis toxicity [12]. With due care such side effects should therefore be rare. Firstdegree AV block can be expected in about one-fifth of patients with angina treated with diltiazem up to 360 mg daily [34].

Opie, Lionel H. "Calcium channel antagonists part IV: Side effects and contraindications drug interactions and combinations." Cardiovascular drugs and therapy 2.2 (1988): 177-189.

eCPS – Supraventricular Tachycardia (2014); Hypertension (2015); Stable angina (2014)

Hypotension is the most common manifestation of CCB overdose. Impaired myocardial contractility and bradycardia are other important features. Verapamil and diltiazem have more pronounced negative inotropic and chronotropic effects than the dihydropyridines (e.g., amlodipine, felodipine and nifedipine). Dihydropyridines are primarily vasodilators, and reflex tachycardia may occur following overdose. Extreme hypotension can lead to lethargy, dizziness, syncope, altered mental status, metabolic acidosis and renal failure. Profound calcium channel blockade inhibits insulin release and can result in hyperglycemia. Seizures have been reported.

Heart Rate Control in Patients with Persistent or Permanent Atrial Fibrillation or Flutter

Most patients will need drugs to achieve rate control, with the exception of some patients with intrinsic AV nodal disease (usually elderly individuals). Pharmacologic control of heart rate should initially be attempted with a beta-blocker or a calcium channel blocker (diltiazem or verapamil) (Table 7). Digoxin is usually inadequate alone for rate control. Because of its potential toxicity, amiodarone should be used only as a last resort.

Table 7: Drug Therapy for Control of Heart Rate in Patients with Supraventricular Tachycardia

Class Drug DosageAdverse Effects

Drug Interactions Comments

Costa

Calcium Channel Blockers, nondihydropyridine

verapamil

Isoptin SR,generics

5–10 mg iv. May give extra 10 mg iv in 30 minUsual starting dose:120 mg/day po; maximum:480 mg/day po. IR given in divided doses TID–QID; SR given daily or divided doses BID

Bradycardia, hypotension, constipation, flushing.

Beta-blockers, digoxin, amiodarone.

Use with caution in patients with HF.

iv:$$$

po:$$

Calcium Channel Blockers, nondihydropyridine

diltiazem

Cardizem CD, Tiazac,Tiazac XC,generics

0.25 mg/kg iv. May give another 0.35 mg/kg ivafter 15 min if necessary180–540 mg/day po. IRgiven in divided doses TID–QID; SR in divided doses BID; CD and Tiazac given daily

Bradycardia, hypotension.

Beta-blockers, digoxin, amiodarone.

Use with caution in patients with HF.

iv$ c :

po:$

Cardiovascular Disorders: Supraventricular Tachycardia; David Birnie, MD and Pablo Nery, MD; Date of Revision: May 2014

Long-acting Calcium Channel Blockers (Hypertension)

Long-acting dihydropyridine CCBs can be used as first-line agents but in practice they are generally used in combination therapy. Short-acting formulations of these agents have caused an increase in cardiovascular events in randomized controlled trials and should not be used. Elderly patients with isolated systolic hypertension and black patients are particularly responsive to CCBs.

The data regarding the use of nondihydropyridine calcium channel blockers17,18 and alpha-blockers in pregnancy is very limited, so these agents are typically deferred or exchanged for other preferred agents.

Class Drug DosageAdverse Effects Drug Interactions Comments Cost

Calcium Channel Blockers, dihydropyridine

amlodipineNorvasc,generics

Initial: 2.5 mg/dayMaximum: 10 mg/dayOnce daily po

Ankle edema, flushing, headache and palpitations.

CYP3A4 substrate (many potential interactions).Strong inhibitors include azole antifungals, protease inhibitors, macrolides and quinidine.Grapefruit juice may increase serum concentrations.

$

Calcium Channel Blockers, dihydropyridine

felodipine, extended-releasePlendil, generics

Initial: 2.5 mg/dayUsual: 10 mg/dayMaximum: 20 mg/dayOnce daily po

Ankle edema, flushing, headache and palpitations.

CYP3A4 substrate (many potential interactions).Strong inhibitors include azole antifungals, protease inhibitors, macrolides and quinidine.Grapefruit juice may increase serum concentrations.

Grapefruit juice causes marked elevations in felodipine serum levels and adverse events.Felodipine does not have Health Canada approval for angina

$$

Calcium Channel Blockers, dihydropyridine

nifedipine, extended-releaseAdalat XL, generics

Initial: 30 mg/dayUsual: 60 mg/dayMaximum: 120 mg/dayOnce daily po

Ankle edema, flushing, headache and palpitations.

CYP3A4 substrate (many potential interactions).Strong inhibitors include azole antifungals, protease inhibitors, macrolides and quinidine.Grapefruit juice may increase serum concentrations.

Do not use short-acting nifedipine formulations for treatment of essential hypertension.

$$

Calcium Channel Blockers, nondihydropyridine

diltiazemCardizem CD, Tiazac, Tiazac XC,generics

Initial: 120 mg/dayUsual:240–360 mg/dayMaximum:360 mg/dayGive CD or XC formulation once daily po, SR formulation divided BID po

Headache, dizziness, bradycardia, heart block, new onset or worsening of heart failure.

CYP3A4 substrate (many potential interactions).Strong inhibitors include azole antifungals, protease inhibitors, macrolides and quinidine.Grapefruit juice may increase serum concentrations.Nondihydropyridines inhibit the metabolism of carbamazepine, cyclosporine, lovastatin, simvastatin.Rifampin induces metabolism of nondihydropyridines.Additive negative inotropic effects with amiodarone, beta-blockers and digoxin.

Caution in patients with heart failure, or 2nd or 3rddegree heart block without a functioning pacemaker.

$$

Calcium Channel Blockers, nondihydropyridine

verapamilIsoptin SR, generics

Initial: 80 mg TID poMaximum:160 mg TID poSR (once daily or divided BID po): Initial: 180 mg/day; Usual: 180–480 mg/day; Maximum: 480 mg/day

Headache, dizziness, bradycardia, heart block, new onset or worsening of heart failure.Constipation.

CYP3A4 substrate (many potential interactions).Strong inhibitors include azole antifungals, protease inhibitors, macrolides and quinidine.Grapefruit juice may increase serum concentrations.Nondihydropyridines inhibit the metabolism of carbamazepine, cyclosporine, lovastatin, simvastatin.Rifampin induces metabolism of nondihydropyridines.Additive negative inotropic effects with amiodarone, beta-blockers and digoxin.Verapamil increases digoxin levels by 50–75% within 1 wk (monitor levels).

Caution in patients with heart failure, or 2nd or 3rddegree heart block without a functioning pacemaker.

$-$$

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Cardiovascular Disorders: Hypertension ; Norm R.C. R. C. Campbell, MD, FRCPC, Paul Gibson, MD, FRCPC, and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of Revision: March 2015

Calcium Channel Blockers (Angina)

Practically speaking, there are 2 classes of calcium channel blockers. The non-dihydropyridines verapamil and diltiazem act more centrally and thus behave similarly to beta-blockers: they decrease myocardial oxygen demand by lowering heart rate, contractility and blood pressure. The dihydropyridines exert their effects primarily by arterial dilation. Amlodipine, felodipine, and nifedipine have been effective in stable angina, though felodipine does not have Health Canada approval for this indication. They reduce blood pressure and, consequently, myocardial oxygen demand. Furthermore, by dilating coronary arteries, dihydropyridines may also increase myocardial oxygen supply

When using a calcium channel blocker to treat angina in a patient who is already on a beta-blocker, a peripherally acting dihydropyridine is preferred; close monitoring of heart rate and AV nodal function is required if verapamil or diltiazem is combined with a beta-blocker.

Note: Chart of medications from eCPS was the same in hypertension and asthma, except felodipine is not indicated for angina.

Cardiovascular Disorders: Stable Angina; Michael Froeschl, MD, MSc, FRCPC, FACC; Date of revision: November 2014

Medication Uses Contraindications (CI), drug interactions (DI) or cautions

Adverse Effects(common and

severe)Initial dose; typical dose Monitoring

verapamil atrial fibrillation, super ventricular arrhythmia, angina – stable, hypertension, cardiomyopathy

CI: WPW syndrome

DI: amiodarone, alcohol, carbamazepine, cyclosporine, digoxin, dofetilide, erythromycin, grapefruit juice, lithium, pimozide, ranolazine, rifampin, simvastatin, terazosin

HF, AV block, constipation

40mg; 40-80mg every 8 hours

LFTs, BP

amlodipine angina - stable, hypertension -variant

DI: grapefruit juice Decrease dose in hepatic insufficiency

hypotension, dizziness, palpitations, lightheadedness, edema ankles/feet, flushing

5mg; 5-10mg one time a day