The Role of Calcium Channel Blockers in Pulmonary Arterial Hypertension: Use of Calcium Channel Blockers in Other Groups of Patients With PAH

Use of Calcium Channel Blockers in Other Groups of Patients With PAH

All of the studies mentioned so far have been conducted in adults with IPAH, but CCB therapy has been evaluated in children with IPAH as well. Barst and colleagues^[21] initially reported the results of acute vasodilator testing and long-term CCB therapy in 74 children (< 16 years old) with IPAH in 1998. They used epoprostenol as their acute testing agent and defined a positive response as a decrease in mPAP ≥ 20%, no change or an increase in cardiac index, and no change or a decrease in the ratio of PVR to systemic vascular resistance. They found that 31 children (42%) were acute responders, a much higher percentage than that found in adult studies. These children had a decrease in mPAP from 57 ± 22 to 38 ± 17 mm Hg and in PVR from 17 ± 11 to 8 ± 6 units, P < .0001 for both (see Table 3 ). As with the studies in adults, acute responders had less severe hemodynamic abnormalities at baseline.

When treated chronically with CCBs, a similar percentage of children and adults (in the study by Sitbon and colleagues) who exhibited acute vasoreactivity demonstrated improvement with long-term CCBs after 5 years of treatment -- 52% and 54%, respectively.^[19] Survival for both groups of long-term responders was identical at 97%. Hemodynamic improvement was also nearly identical, with a decrease in mPAP to 31 ± 15 mm Hg in children and 35 ± 7 mm Hg in adults with IPAH. In children, lower baseline mPAP was the only hemodynamic variable predictive of improvement with CCB therapy, P = .022.

When this group of children was followed an additional 5 years, however, the percentage of long-term CCB responders decreased to 32%, and survival, despite the availability of epoprostenol and lung transplantation, decreased to 81% at 10 years.^[22] This may be related to fact that children appear to have less vasoreactivity as they get older so that older children have a response rate similar to that reported for adults (see Figure 7). This is also supported by the fact that 14/31 children (45%) who were found to be vasoreactive at baseline became nonresponsive to acute vasodilator testing at follow-up. Baseline hemodynamics did not predict loss of vasoreactivity, nor did reclassification of acute responders using the more recent ESC guidelines.^[20] Further, a change from acute responder to nonresponder increased the risk of treatment failure with chronic CCB therapy by a factor of 8.97 (95% CI, 2.54 to 31.74, P = .007).

Figure 7.

Enlarge

Response to short-term testing by age. The younger the child at the time of testing, the greater the likelihood of eliciting short-term pulmonary vasodilation (P < .005).
Used with permission from: Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.

Small studies with CCBs have been done in other groups of patients with PAH. Nootens and colleagues^[23] performed acute vasodilator testing with high-dose CCBs in 21 patients with PAH due to a variety of causes including liver disease, connective tissue disease (CTD), and congenital heart disease. They found that only 1 patient had a substantial reduction in mPAP and PVR. Long-term administration of CCBs was not assessed in this group but, based on the poor acute response, would almost certainly have been ineffective.

The only group of PAH patients in whom chronic treatment with CCBs has been evaluated are patients with CTD. Although CCBs have been used extensively to treat Raynaud's phenomenon, the largest study in PAH associated with CTD involves only 10 patients, 6 with limited cutaneous scleroderma and 3 with mixed connective tissue disease. Alpert and colleagues^[24] reported a decrease in mPAP from 42 ± 18 to 31 ± 18 mm Hg and a reduction in PVR from 6.3 ± 2.7 to 4.3 ± 3.8 units (P < .001 for both) with acute vasodilator testing during which patients were given up to 30 mg of nifedipine over 90 minutes. Six patients received long-term treatment with CCBs, demonstrating similar hemodynamic improvement at follow-up evaluation 3 to 6 months later. Our experience has been that while some patients with scleroderma demonstrate acute vasoreactivity in response to NO, they do not experience long-term benefit from CCBs. On the basis of expert opinion only, recent recommendations by the ACCP for acute vasodilator testing in patients with PAH stated that the benefit was minimal other than for those patients with IPAH or familial PAH.^[18]