Two calcium channel blockers better than one?

Many of us may have become so adept at treating hypertension that we may believe that, while they can give us new drugs, they really can’t teach us any new tricks.

So, stop me if you’ve heard this one: two calcium channel blockers (CCBs) at the same time.

We are aware that dual-agent therapy is likely more efficacious than up-titration of monotherapy. The antihypertensive effect of two drugs from different classes may be five times greater than that of the doubling of monotherapy. But what about two different drugs of the same class, such as CCBs?

CCBs are either dihydropyridines (DHPs) (that is, amlodipine) or nondihydropyridines (NDHPs) (that is, verapamil). Dr. Carlos Alviar and his colleagues conducted a systematic review evaluating the efficacy and safety of dual CCBs for the treatment of hypertension (Am. J. Hypertens. 2013;26:287-97).

The authors searched for clinical trials published between 1966 and 2012. Included studies were required to be randomized, evaluate dual-agent therapy with monotherapy, use equivalent doses, and treat for longer than 1 week. The primary efficacy outcome was the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between study groups. Safety outcomes included the risk of adverse events.

Six studies satisfied inclusion criteria. A significant SBP reduction was observed of 10.9 mm Hg more with dual CCB than with a DHP alone (P less than .01) or 14 mm Hg more than with a NDHP alone (P = .002). Dual CCB therapy reduced DBP 5.5 mm Hg more than did a DHP alone (P less than .001), and by 5.3 mm Hg more than with a NDHP alone (P = .03). Mean heart rate changes from baseline were –4.0, 2.0, and –6.0 beats/minute with dual CCB therapy, DHP, and NDHP, respectively.

No significant increases in edema, headache, or flushing were observed with dual CCB therapy. Notably, constipation was lower with dual CCB than with NDHP alone.

The drugs may be synergistic because of the negative inotropic and chronotropic effects of the NDHP and the vasodilatory effect of the DHP, or they simply could be additive. The National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group includes dual CCB therapy among one of the recommended treatment approaches for hypertension. However, some guidelines do not recommend this approach including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the American Society of Hypertension.

The long-term effects of this combination are uncertain, and the impact of dual CCB therapy on cardiovascular morbidity and mortality beyond that of monotherapy is uncertain. But for select patients with hard to control blood pressure, this approach might be a strategy before trying to find a pharmacy that dispenses methyldopa.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts.

This column, "What Matters," appears regularly in Internal Medicine News, a publication of IMNG Medical Media.

Many of us may have become so adept at treating hypertension that we may believe that, while they can give us new drugs, they really can’t teach us any new tricks.

So, stop me if you’ve heard this one: two calcium channel blockers (CCBs) at the same time.

We are aware that dual-agent therapy is likely more efficacious than up-titration of monotherapy. The antihypertensive effect of two drugs from different classes may be five times greater than that of the doubling of monotherapy. But what about two different drugs of the same class, such as CCBs?

CCBs are either dihydropyridines (DHPs) (that is, amlodipine) or nondihydropyridines (NDHPs) (that is, verapamil). Dr. Carlos Alviar and his colleagues conducted a systematic review evaluating the efficacy and safety of dual CCBs for the treatment of hypertension (Am. J. Hypertens. 2013;26:287-97).

The authors searched for clinical trials published between 1966 and 2012. Included studies were required to be randomized, evaluate dual-agent therapy with monotherapy, use equivalent doses, and treat for longer than 1 week. The primary efficacy outcome was the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between study groups. Safety outcomes included the risk of adverse events.

Six studies satisfied inclusion criteria. A significant SBP reduction was observed of 10.9 mm Hg more with dual CCB than with a DHP alone (P less than .01) or 14 mm Hg more than with a NDHP alone (P = .002). Dual CCB therapy reduced DBP 5.5 mm Hg more than did a DHP alone (P less than .001), and by 5.3 mm Hg more than with a NDHP alone (P = .03). Mean heart rate changes from baseline were –4.0, 2.0, and –6.0 beats/minute with dual CCB therapy, DHP, and NDHP, respectively.

No significant increases in edema, headache, or flushing were observed with dual CCB therapy. Notably, constipation was lower with dual CCB than with NDHP alone.

The drugs may be synergistic because of the negative inotropic and chronotropic effects of the NDHP and the vasodilatory effect of the DHP, or they simply could be additive. The National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group includes dual CCB therapy among one of the recommended treatment approaches for hypertension. However, some guidelines do not recommend this approach including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the American Society of Hypertension.

The long-term effects of this combination are uncertain, and the impact of dual CCB therapy on cardiovascular morbidity and mortality beyond that of monotherapy is uncertain. But for select patients with hard to control blood pressure, this approach might be a strategy before trying to find a pharmacy that dispenses methyldopa.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts.

This column, "What Matters," appears regularly in Internal Medicine News, a publication of IMNG Medical Media.

Many of us may have become so adept at treating hypertension that we may believe that, while they can give us new drugs, they really can’t teach us any new tricks.

So, stop me if you’ve heard this one: two calcium channel blockers (CCBs) at the same time.

We are aware that dual-agent therapy is likely more efficacious than up-titration of monotherapy. The antihypertensive effect of two drugs from different classes may be five times greater than that of the doubling of monotherapy. But what about two different drugs of the same class, such as CCBs?

CCBs are either dihydropyridines (DHPs) (that is, amlodipine) or nondihydropyridines (NDHPs) (that is, verapamil). Dr. Carlos Alviar and his colleagues conducted a systematic review evaluating the efficacy and safety of dual CCBs for the treatment of hypertension (Am. J. Hypertens. 2013;26:287-97).

The authors searched for clinical trials published between 1966 and 2012. Included studies were required to be randomized, evaluate dual-agent therapy with monotherapy, use equivalent doses, and treat for longer than 1 week. The primary efficacy outcome was the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between study groups. Safety outcomes included the risk of adverse events.

Six studies satisfied inclusion criteria. A significant SBP reduction was observed of 10.9 mm Hg more with dual CCB than with a DHP alone (P less than .01) or 14 mm Hg more than with a NDHP alone (P = .002). Dual CCB therapy reduced DBP 5.5 mm Hg more than did a DHP alone (P less than .001), and by 5.3 mm Hg more than with a NDHP alone (P = .03). Mean heart rate changes from baseline were –4.0, 2.0, and –6.0 beats/minute with dual CCB therapy, DHP, and NDHP, respectively.

No significant increases in edema, headache, or flushing were observed with dual CCB therapy. Notably, constipation was lower with dual CCB than with NDHP alone.

The drugs may be synergistic because of the negative inotropic and chronotropic effects of the NDHP and the vasodilatory effect of the DHP, or they simply could be additive. The National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group includes dual CCB therapy among one of the recommended treatment approaches for hypertension. However, some guidelines do not recommend this approach including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the American Society of Hypertension.

The long-term effects of this combination are uncertain, and the impact of dual CCB therapy on cardiovascular morbidity and mortality beyond that of monotherapy is uncertain. But for select patients with hard to control blood pressure, this approach might be a strategy before trying to find a pharmacy that dispenses methyldopa.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts.

This column, "What Matters," appears regularly in Internal Medicine News, a publication of IMNG Medical Media.