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

Use of High-Dose CCBs in the Treatment of PAH

Due to the modest decrease in mPAP and the failure to improve outcomes (compared with untreated patients) in a previous study using conventional doses of CCBs, Rich and Brundage^[8] studied the effects of higher doses of CCBs in patients with IPAH.^[9] Thirteen consecutive patients were acutely tested using a new protocol: patients received hourly doses of nifedipine (20 mg) or diltiazem (60 mg), if the heart rate was > 100 bpm, until a positive response was obtained or until the patient experienced adverse side effects. A positive response was defined very stringently in this study as greater than a 50% reduction in PVR as well as a 33% decrease in mPAP. There was essentially no hemodynamic change in any patient after a single dose of CCB. However, with repeated doses of CCBs, the investigators achieved a mean decrease in mPAP of 36% and in PVR of 49% in 8 of the 13 patients. All but 1 of the responders had a decrease in mPAP to < 40 mm Hg and a reduction in PVR to < 7 units, (See Figures 1 and 2). Interestingly, there was a significantly greater fall in systemic arterial pressure in nonresponders compared with the 8 responders, 22% vs 12%, respectively (P < .05), suggesting a preferential effect of CCBs on the pulmonary circulation in responders.

Figure 1.

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The initial mean pulmonary arterial pressure (mPAP) and the responses to conventional and high-dose calcium channel blockers are illustrated. All but 1 of the responders had decreases in their mPAP to 40 mm Hg or lower. The 1 nonresponder who had reduction in mPAP also had systemic hypotension concomitantly.
Used with permission from: Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation. 1987;76:135-141.

Figure 2.

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The effect of the treatment regimen on pulmonary vascular resistance, with the patients classified as responders or nonresponders. All but 1 of the responders had a reduction in pulmonary vascular resistance to 7 Wood units (WU) or less with high-dose therapy.
Used with permission from: Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation. 1987;76:135-141.

The 8 patients exhibiting an acute response were then given the cumulative dose of CCB that produced maximal hemodynamic benefit every 6-8 hours, as tolerated. Chronic treatment doses ranged from 120-240 mg of nifedipine and 240-720 mg of diltiazem daily. Five patients returned for repeat hemodynamic evaluation after 1 year of treatment, all of whom had sustained improvement in symptoms, functional class, and hemodynamics. Four of the 5 patients had a sustained decrease in mPAP greater than or equal to that achieved at the time of acute testing. The other patient had halved her dose of nifedipine due to side effects and still exhibited long-term, but less pronounced, hemodynamic improvement. Although this was not a randomized trial, the results suggested that patients with IPAH could have marked hemodynamic improvement with chronic CCB therapy if treated with a higher dose than that given for the treatment of systemic hypertension.

In 1992, Rich and colleagues^[10] published what remains the largest prospective study of IPAH patients chronically treated with CCBs. They evaluated 71 patients, 7 of whom had evidence of severe right heart failure, defined as a right atrial pressure > 20 mm Hg and a cardiac output < 2 L/min. These patients were excluded from acute testing. The remaining 64 patients underwent acute testing with CCBs and were studied for up to 5 years. A positive response was defined less strictly in this study as a decrease in both PVR and mPAP of > 20%. However, in the 17 patients (26.5%) who exhibited a positive response, there was a mean decrease in mPAP of 39% and a mean decrease in PVR of 53%. All of the 17 patients who exhibited an acute CCB response improved clinically with long-term, high-dose CCB therapy (average doses of 172 ± 41 mg of nifedipine or 720 ± 208 mg of diltiazem), and nearly all of them demonstrated sustained hemodynamic improvement (see Figure 3). Most impressively, at the conclusion of the observation period, survival was markedly better in CCB responders, 94% vs 55% in those patients who did not exhibit acute vasoreactivity and were not treated with CCBs; P < .003 (see Figure 4).

Figure 3.

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Mean pulmonary artery pressure and pulmonary vascular resistance index in the patients who had favorable responses. Values shown were measured at baseline, after initial assessment of the effectiveness of the drug, and then periodically for up to 5 years.
Used with permission from: Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary hypertension. N Engl J Med. 1992;327:76-81.

Figure 4.

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Kaplan-Meier estimates of survival among patients who responded to treatment (open circles), those who did not respond (solid lines), patients enrolled in the National Institutes of Health (NIH) Registry who were treated at the University of Illinois (solid circles), and the NIH Registry Cohort (triangles). The percentages were calculated every 6 months for 5 1/2 years. The rate of survival was significantly better among treatment responders (P = .003) than in the other groups.
Used with permission from: Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary hypertension. N Engl J Med. 1992;327:76-81.

Although the results of the study by Rich and colleagues were impressive, no subsequent study has found as high a percentage of responders to CCB therapy. This may reflect the fact that patients in the community who are treated successfully with CCBs are never seen at a major referral center. Another explanation may be that with the availability of additional therapies for the treatment of PAH, fewer patients are being tried on CCBs. Other shortcomings of this study include the small number of patients, the lack of a placebo arm in acute responders treated chronically with CCBs, and the anticoagulation of many, but not all, patients in a nonrandomized fashion.