What is the relationship between Calcium Channel Blockers (CCBs) and peripheral edema?

From the Guidelines

Calcium Channel Blockers (CCBs) are known to cause peripheral edema in approximately 5-30% of patients, with the most recent and highest quality study suggesting that this side effect is common to all CCBs 1. The relationship between CCBs and peripheral edema is well-established, with the mechanism involving vasodilation of peripheral blood vessels, increased hydrostatic pressure in capillaries, and subsequent fluid leakage into surrounding tissues. Some key points to consider:

• The incidence of peripheral edema varies among different CCBs, with amlodipine tends to cause more edema than diltiazem or verapamil 1.
• Management options for peripheral edema include elevating the legs, reducing salt intake, wearing compression stockings, switching to a different CCB or antihypertensive medication, or adding a diuretic like hydrochlorothiazide (12.5-25mg daily) 1.
• It is essential to consult a healthcare provider before stopping or changing any medication, as uncontrolled hypertension poses greater risks than edema.
• The most recent study 1 provides the most up-to-date information on the relationship between CCBs and peripheral edema, and its findings should be prioritized in clinical decision-making. Key considerations for managing peripheral edema in patients taking CCBs include:
• Monitoring for signs and symptoms of edema
• Adjusting medication regimens as needed to minimize edema
• Educating patients on lifestyle modifications to reduce edema, such as elevating the legs and reducing salt intake.

From the FDA Drug Label

The incidence (%) of side effects that occurred in a dose related manner are as follows: ... Edema 1.8 3.0 10.8 0.6 For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: ... Edema 5.6 14.6 1.4 5.1 In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)] , the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

The relationship between Calcium Channel Blockers (CCBs), specifically Amlodipine, and peripheral edema is that peripheral edema is a common adverse event associated with Amlodipine treatment, with a dose-related incidence of 1.8% to 10.8% in clinical trials 2. The incidence of peripheral edema is also greater in women than men, with 14.6% of women experiencing this side effect compared to 5.6% of men 2. Peripheral edema was the most common adverse event in the CAMELOT and PREVENT studies 2.

• Key points:
  • Peripheral edema is a common adverse event associated with Amlodipine treatment
  • The incidence of peripheral edema is dose-related
  • The incidence of peripheral edema is greater in women than men
  • Peripheral edema was the most common adverse event in the CAMELOT and PREVENT studies 2

From the Research

Relationship Between Calcium Channel Blockers (CCBs) and Peripheral Edema

• CCBs are effective antihypertensive agents, but their propensity for causing peripheral edema may reduce compliance 3.
• The incidence of peripheral edema with CCBs can be as high as 25% in some cases, and is caused by increased capillary hydrostatic pressure resulting from preferential dilation of pre-capillary vessels 3.
• The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way 4.

Incidence and Withdrawal Rate of Peripheral Edema

• The weighted incidence of peripheral edema was significantly higher in the CCBs group when compared with controls/placebo (10.7 vs. 3.2%, P < 0.0001) 5.
• The withdrawal rate due to edema was higher in patients on CCBs compared with control/placebo (2.1 vs. 0.5%, P < 0.0001) 5.
• Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with CCBs, reaching 24 and 5%, respectively, after 6 months 5.

Strategies to Reduce Peripheral Edema

• Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in combination with a dihydropyridine calcium channel blocker may be helpful in reducing peripheral edema 6, 7.
• Some calcium channel blockers may be less likely to cause peripheral edema compared with others, with lipophilic DHPs having a 57% lower risk of edema compared to traditional DHPs 5.
• Reducing the dosage of CCBs or switching to a different class of CCBs may also help to reduce peripheral edema 7.

Comparison of Different CCBs

• The risk of peripheral edema with lipophilic DHPs was 57% lower than with traditional DHPs (relative risk 0.43; 95% confidence interval 0.34-0.53; P < 0.0001) 5.
• Incidence of peripheral edema in patients on DHPs was 12.3% compared with 3.1% with non-DHPs (P < 0.0001) 5.
• Edema with high-dose CCBs was 2.8 times higher than that with low-dose CCBs (16.1 vs. 5.7%, P < 0.0001) 5.