The Role of Calcium Channel Blockers in Pulmonary Arterial Hypertension: Current Use of CCBs in the Treatment of PAH

Current Use of CCBs in the Treatment of PAH

Three CCBs are presently used in the treatment of patients with PAH: nifedipine, diltiazem, and, increasingly, amlodipine. Nifedipine and diltiazem have been studied in numerous clinical studies as documented above, with the use of the latter most often dictated by the presence of a resting tachycardia, which may be exacerbated by nifedipine. Other than 2 patients in the study by Sitbon and colleagues, there are no studies specifically evaluating the long-term effects of amlodipine in acute vasodilator responders. One small short-term study in 6 patients with pulmonary hypertension (5 with chronic thromboembolic disease and one with IPAH) showed that amlodipine, up to a dose of 40 mg, was well tolerated.^[25] There was also a decrease in mPAP and PVR of > 20% with mild effects on systemic blood pressure in 2 patients. The use of amlodipine for long-term treatment is based in part on the efficacy and safety shown in patients with congestive heart failure, and perhaps on its long half-life, which may provide additional safety from the hemodynamic deterioration that may occur after acute CCB withdrawal.^[26]We generally initiate therapy with amlodipine and change to another CCB if patients do not tolerate amlodipine, which is not infrequently associated with the development of lower extremity edema, even at conventional doses. This side effect may also occur with other CCBs when titrated to high doses. Other side effects that may occur with high-dose CCB therapy, and which may limit dose titration, include hypotension, bradycardia, gastrointestinal upset, headache, and constipation.

Although impressive long-term results with high doses of CCBs have been obtained in some patients, whether conventional doses in patients with PAH would be as efficacious has not been studied. No randomized study has been conducted comparing treatment with low- vs high-dose CCBs in PAH. The recommendation for the use of high-dose CCBs for chronic treatment was based on the dose required for an acute vasodilator effect. Despite a high average dose of CCBs reported in the study by Sitbon and colleagues, the doses of nifedipine and diltiazem ranged from 60 to 120 mg daily and 180 to 720 mg, respectively, indicating that some of their patients had long-term improvement with conventional doses of CCBs.^[19] This has been our experience as well.

Few large centers currently admit patients for dose titration of CCBs. In most cases, patients who exhibit an acute vasodilator response based on the recent ESC criteria are started on a low dose of CCBs as an outpatient, for example, 30 mg of nifedipine or 2.5 mg of amlodipine. Patients are then gradually up-titrated as an outpatient at regular intervals. At our center, we increase the dose weekly by 30 mg of nifedipine or 2.5 mg of amlodipine and either have patients return for a blood pressure reading or have their blood pressure checked locally. Frequent telephone contact is maintained with patients who are instructed to report any side effects as soon as they occur.

Although up-titration protocols vary from center to center, the key point is that patients must be followed closely, both for safety and efficacy. Follow-up clinical evaluation with some measure of exercise capacity (most often 6-minute walk distance) should be performed within 3 months of initiating therapy. Depending upon the institution, additional evaluation may be performed at this time such as echocardiogram or even repeat invasive hemodynamic evaluation. Our preference in patients who are clinically and symptomatically improved with CCB therapy is to perform a repeat right heart catheterization after 1 year of therapy to document maintenance of hemodynamic improvement. Additional therapy must be considered in patients failing to improve or worsening with CCB therapy.