CALCIUM CHANNEL BLOCKERS















Overview
  • CCBs are widely used to treat hypertension
  • Diltiazem and verapamil (nondihydropyridines) have been around for a long time, and studies evaluating their BP-lowering effects are sparse. A randomized controlled trial that compared the effects of 6 different BP meds including diltiazem is detailed below. We found no good information for verapamil.
  • A Cochrane meta-analysis that looked at the BP-lowering effects of dihydropyridine CCBs is also presented below
Diltiazem vs Others, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with diltiazem was similar to placebo

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
Blood Pressure Lowering with dihydropyridine CCBs, Cochrane meta-analysis (2014) [PubMed abstract]
  • A Cochrane meta-analysis evaluated the effects of dihydropyridine CCBs on blood pressure in patients with hypertension
  • The analysis included 16 randomized placebo-controlled trials (N=2768) that used amlodipine, lercanidipine, manidipine, nifedipine, felodipine, or nicardipine
Results

Average hourly BP reduction (CCB minus Placebo)
SBP 9.5 - 13.2 mmHg
DBP 5.9 - 8.5 mmHg

Professional recommendations
  • See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations



Overview
  • Two studies that evaluated the effects of CCBs on cardiovascular outcomes are presented below
  • In the ALLHAT trial, the effect of amlodipine was compared to lisinopril and chlorthalidone in patients with hypertension
  • A Cochrane meta-analysis compared cardiovascular outcomes with CCBs to other classes of blood pressure medications in patients with hypertension
ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD, JAMA (2002) [PubMed abstract]
  • The ALLHAT study enrolled 33,357 patients with hypertension and at least one risk factor for heart disease
Main inclusion criteria
  • Age > 55 years
  • SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
  • One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
  • History of hospitalized or treated symptomatic heart failure
  • EF < 35%
Baseline characteristics
  • Average age 67 years
  • Race: White - 47% | Black - 32% | Hispanic - 16%
  • Women - 47%
  • Average BP - 146/84
  • Receiving treatment for hypertension - 90%
  • Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
  • Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
  • Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
  • Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
  • Treatment was titrated to a BP goal of < 140/90
  • If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
  • There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results

Duration: Average of 4.9 years
Outcome Chlorthalidone Amlodipine Lisinopril Comparisons
Primary outcome (6-year rate) 11.5% 11.3% 11.4% 1 vs 2 p=0.65 | 1 vs 3 p=0.81
Overall mortality (6-year rate) 17.3% 16.8% 17.2% 1 vs 2 p=0.20 | 1 vs 3 p=0.90
Stroke (6-year rate) 5.6% 5.4% 6.3% 1 vs 2 p=0.28 | 1 vs 3 p=0.02
Heart failure (6-year rate) 7.7% 10% 8.7% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Achieved BP goal (< 140/90) at 1 year 57.8% 55.2% 50.6% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Potassium < 3.5 mEq/L at 2 years 12.7% 2.6% 1.5% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
New-onset diabetes at 4 years 11.6% 9.8% 8.1% 1 vs 2 p=0.04 | 1 vs 3 p<0.001

Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
CCBs vs Other BP Meds for CVD, Cochrane meta-analysis (2010) [PubMed abstract]
  • A Cochrane meta-analysis compared cardiovascular outcomes with CCBs to those of other blood pressure medications in patients with hypertension
  • Dihydropyridines were used in 14 of the trials and nondihydropyridines were used in 4
  • Other blood pressure medications included thiazide diuretics, beta blockers, ACE inhibitors, and ARBs
Results
  • For overall mortality, there was no significant difference between CCBs and the other medications
  • Risk of a heart attack was significantly lower with CCBs when compared to ARBs (relative risk reduction 17%)
  • Risk of stroke was significantly lower with CCB when compared to beta blockers (relative risk reduction 23%), ACE inhibitors (relative risk reduction 11%), and ARBs (relative risk reduction 15%)
  • Risk of heart failure was significantly worse with CCB when compared to diuretics (relative risk increase 37%), ACE inhibitors (relative risk increase 16%), and ARBs (relative risk increase 20%) [6]
Summary
  • CCBs appear to be better than other medications at preventing stroke. This is consistent with the fact that stroke risk is closely tied to blood pressure, and CCBs tend to have a more consistent effect on blood pressures across different patient populations than other meds (ex. beta blockers, ACE inhibitors, ARBs). [1]
  • CCBs appear to be worse than other medications in preventing heart failure. This is consistent with the fact that other medications are beneficial in heart failure (ex. diuretics, beta blockers, ACE inhibitors), where CCBs have no proven benefit.






Overview
  • Stable angina is predictable and reproducible cardiac chest pain that occurs with exertion and is relieved with rest
  • Most studies evaluating CCBs in the treatment of stable angina are small and older
  • We found one meta-analysis that compared different treatments for stable angina
CCBs vs Beta Blockers vs Nitrates for Stable Angina, JAMA meta-analysis (1999) [PubMed abstract]
  • A JAMA meta-analysis from 1999 evaluated trials that compared CCBs to nitrates or beta blockers in the treatment of stable angina
  • Nifedipine, verapamil, or diltiazem were the CCBs predominantly used in the trials evaluated
When CCBs were compared to beta blockers, the following results were seen:
  • Compared to calcium channel blockers, beta blockers were associated with 0.31 fewer episodes of angina per week (borderline significant, p=0.05)
  • There was no significant difference in a composite outcome of heart attack or cardiac death
  • There was no significant difference in nitroglycerin use per week
  • CCBs were associated with a greater number of adverse events than beta blockers
When CCBs were compared to long-acting nitrates, the following results were seen:
  • There was no significant difference between groups for any outcome [28]
Findings: Beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina
AHA recommendations
  • The AHA 2012 CAD guidelines recommend beta blockers as the first-line agent for the treatment of chronic angina
  • If beta blockers are contraindicated or not tolerated, then calcium channel blockers (dihydropyridines and nondihydropyridines) or long-acting nitrates should be used
  • If initial beta blocker therapy does not control symptoms, then a calcium channel blocker or long-acting nitrate should be added to beta blocker therapy [59]
StraightHealthcare analysis
  • Beta blockers are the preferred first-line agent in chronic angina because they improve heart failure outcomes
  • Calcium channel blockers and long-acting nitrates are also effective
  • Nifedipine and diltiazem should be used with caution in patients with heart failure because they may worsen outcomes. Amlodipine has been shown to be safe in heart failure.









Overview
  • Heart failure with reduced ejection fraction (HFrEF), also called "systolic heart failure," is heart failure caused by a reduced ability of the left side of the heart to pump blood effectively which leads to a reduced ejection fraction (compare to HFpEF where ejection fraction is preserved)
  • Nondihydropyridines CCBs (diltiazem and verapamil) can decrease the force of heart contraction and worsen heart failure in some patients. For this reason, diltiazem and verapamil should generally be avoided in patients with systolic heart failure. Dihydropyridine CCBs do not generally have this effect. The PRAISE study detailed below was specifically designed to look at the safety of amolodipne in patients with HFrEF.
PRAISE study - Amlodipine vs Placebo in Severe Heart Failure, NEJM (1996) [PubMed abstract]
  • The PRAISE study enrolled 1153 patients with severe heart failure
Main inclusion criteria
  • NYHA class III or IV heart failure
  • EF < 30%
Main exclusion criteria
  • SBP < 85 or > 159
  • DBP > 89
  • Serum creatinine > 3 mg/dl
  • Treatment with beta blockers
  • Treatment with CCB
Baseline characteristics
  • Average age 64 years
  • NYHA class: III - 81% | IV - 19%
  • Average BP - 117/72
  • Average EF - 21%
Randomized treatment groups
  • Group 1 (571 patients) Amlodipine once daily with a target dose of 10 mg (average dose achieved was 8.8 mg)
  • Group 2 (582 patients) Placebo once daily
  • Almost all patients in the study were taking digoxin, an ACE inhibitor, and diuretics
  • Randomization was stratified by type of heart failure - ischemic or nonischemic dilated cardiomyopathy
Primary outcome: Composite of death from any cause or hospitalization for major cardiovascular event defined as acute pulmonary edema, severe hypoperfusion, acute myocardial infarction, or sustained or hemodynamically destabilizing ventricular tachycardia or fibrillation
Results

Duration: Median of 13.8 months
Outcome Amlodipine Placebo Comparisons
Primary outcome 39% 42% p=0.31
Overall mortality 33% 38% p=0.07
Peripheral edema 27% 18% p<0.05
Pulmonary edema 15% 10% p<0.05
Drug discontinuation 14.4% 16% N/A
  • In the subgroup of patients with nonischemic dilated cardiomyopathy, amlodipine improved both the primary outcome (p=0.04) and overall survival (p<0.001) when compared to placebo
  • The amlodipine group achieved a significantly lower BP than the placebo group at 3 months (SBP and DBP lower by 2 mmHg)

Findings: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.
Professional guidelines:
  • The AHA/ACC recommends that diltiazem and verapamil not be used in patients with heart failure
  • They state that amlodipine has not been shown to adversely affect survival
StraightHealthcare analysis
  • Diltiazem and nifedipine should be avoided in most patients with heart failure
  • In patients whose blood pressure is not controlled with preferred agents (beta blockers, ACE inhibitors, ARBs, and diuretics), amlodipine appears to be a safe option






Slow heart rate (bradycardia)

Swelling of the legs and feet (peripheral edema)

Constipation (verapamil)

Gingival hyperplasia (overgrowth of the gums)
BJCP case-control study StraightHealthcare analysis

Flushing (warm feeling of the face)

First degree heart block






Kidney disease
Amlodipine (Norvasc®) Diltiazem (Cardizem®, etc.) Felodipine (Plendil®) Isradipine (Dynacirc®) Nicardipine (Cardene®) Nifedipine (Procardia®, etc.) Nisoldipine (Sular®) Verapamil (Calan®, etc.)

Liver disease
Amlodipine (Norvasc®) Diltiazem (Cardizem®, etc.) Felodipine (Plendil®) Isradipine (Dynacirc®) Nicardipine (Cardene®) Nifedipine (Procardia®, etc.) Nisoldipine (Sular®) Verapamil (Calan®, etc.)

Heart failure

Heart attack / unstable angina
StraightHealthcare analysis

Second and third degree heart block

Sick sinus syndrome

A fib or flutter with an accessory bypass tract (ex. Wolff-Parkinson-White syndrome)

Hypertrophic cardiomyopathy

Neuromuscular conditions



Drug interactions

All CCBs
  • Clarithromycin (Biaxin®) - Hypotension and acute kidney injury have been reported in patients taking CCBs with the antibiotic clarithromycin. Most reports have occurred in patients ≥ 65 years [55]
  • Nitroglycerin - marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination [54]

Amlodipine (Norvasc®)
  • Cyclosporine - amlodipine may increase cyclosporine levels. Monitor cyclosporine levels closely.
  • CYP3A4 inhibitors - amlodipine is a sensitive CYP3A4 substrate. Moderate and strong CYP3A4 inhibitors may increase exposure to amlodipine and lead to hypotension and/or edema. Monitor patients closely when combining.
  • Simvastatin (Zocor®) - Simvastatin dose should not exceed 20 mg/day while taking amlodipine
  • Tacrolimus - tacrolimus blood levels may increase when taken with amlodipine. Monitor tacrolimus blood levels and adjust dose accordingly.

Diltiazem (Cardizem®, Cartia®, Dilacor®, Taztia®, etc)
  • CYP3A inhibitors/inducers/substrates - may affect the metabolism of diltiazem and vice versa
  • Digoxin - diltiazem may increase digoxin levels. Monitor digoxin levels when starting or changing diltiazem therapy.
  • Ivabradine (Corlanor®) - diltiazem may increase blood levels of ivabradine and cause severe bradycardia. Diltiazem should not be given with ivabradine.
  • Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
  • Medications that slow the heart rate
  • Simvastatin (Zocor®) - Simvastatin dose should not exceed 10 mg/day. Diltiazem dose should not exceed 240 mg/day.
  • Topiramate (Topamax®) - topiramate may decrease diltiazem levels, and diltiazem may increase topiramate levels

Felodipine (Plendil®)

Isradipine (Dynacirc®)
  • Cimetidine - cimetidine may increase exposure to isradipine. Monitor for adverse events and adjust dose if necessary.
  • Rifampicin - rifampicin may decrease exposure to isradipine. Concomitant use is not recommended.

Nicardipine (Cardene®)
  • Cyclosporine - nicardipine inhibits cyclosporine metabolism and increases its exposure. Monitor cyclosporine levels closely when given concomitantly.
  • Tacrolimus - nicardipine inhibits tacrolimus metabolism and increases its exposure. Monitor tacrolimus levels closely when given concomitantly.

Nifedipine (Adalat®, Procardia®, etc)

Nisoldipine (Sular®)

Verapamil (Calan®, Isoptin®, Verelan®)
  • CYP3A inhibitors/inducers/substrates - may affect the metabolism of verapamil and vice versa
  • Digoxin - verapamil may increase digoxin levels. Monitor digoxin levels when starting or changing verapamil therapy.
  • Disopyramide (Norpace®) - Manufacturer recommends disopyramide not be administered 48 hours before or 24 hours after verapamil is administered
  • Ethanol (beverage alcohol) - verapamil may inhibit the metabolism and ethanol and increase blood alcohol levels
  • Ivabradine (Corlanor®) - verapamil may increase blood levels of ivabradine and cause severe bradycardia. Verapamil should not be given with ivabradine.
  • Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
  • Medications that slow the heart rate
  • Oxcarbazepine (Trileptal®) - verapamil may decrease oxcarbazepine levels by 20%
  • P-glycoprotein substrates/inducers/inhibitors - may affect the metabolism of verapamil and vice versa
  • mTOR inhibitors (e.g. temsirolimus, sirolimus, everolimus) - verapamil increases blood levels of mTOR inhibitors and mTOR inhibitors increase blood levels of verapamil. Consider reducing doses of both medications when using together.
  • Simvastatin (Zocor®) - simvastatin dose should not exceed 10 mg/day while taking verapamil


  • Reference: Manufacturer's PI
CCB metabolism and clearance
Drug CYP1A2 CYP2D6 CYP2C8 CYP2C19 CYP3A4 P-glycoprotein
Amlodipine - - - - Sensitive substrate and weak inhibitor -
Diltiazem - Weak inhibitor - - Substrate and inhibitor Substrate and inhibitor
Felodipine - - - - Substrate Substrate
Isradipine - - - - Substrate and inhibitor -
Nicardipine - Substrate and inhibitor Substrate and inhibitor Inhibitor Substrate and weak inhibitor Inhibitor
Nifedipine - - - - Substrate and inhibitor -
Nisoldipine - - - - Substrate -
Verapamil Substrate and weak inhibitor Weak inhibitor Substrate - Substrate and inhibitor Substrate and inhibitor

Medications that slow the heart rate

Overview
  • Verapamil and diltiazem slow the heart rate. When they are taken with other medications that slow the heart rate, bradycardia (< 50 beats per minute) may occur.

Common medications that slow the heart rate