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Table 1.  

Clinical Characteristics, Baseline Hemodynamics, and Exercise Capacity of the Studied Patient Sample

Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Table 2.  

Acute NO/Epoprostenol Responders Group (n = 70) Long-term CCB Responders Group (n = 38) CCB Failure Group (n = 32) P*
Drug tested (NO:epoprostenol) (n) 57:13 33:5 24:8 .2
Mean PAP reached during acute vasodilator testing (mm Hg) 38 ± 11 (18-65) 33 ± 8 (18-50) 46 ± 10 (18-65) < .001
Fall in mean PAP during acute vasodilator testing (mm Hg) 19 ± 7 (10-36) 21 ± 7 (10 - 36) 16 ± 6 (10 - 33) .006
Percent fall in mean PAP 33 ± 11 (20-59) 39 ± 11 (20 - 59) 26 ± 7 (20 - 49) < .001
PVR reached during acute vasodilator testing (WU) 6.6 ± 3.4 (1.1 - 17.4) 5.2 ± 2.7 (1.1 - 13.1) 8.6 ± 3.3 (1.1 - 17.4) < .001
Fall in PVR during acute vasodilator testing (WU) 5.6 ± 3.3 (1.6 - 16.7) 5.1 ± 3.1 (1.7 - 15.4) 6.2 ± 3.4 (1.6 -16.7) .16
Percent fall in PVR 45 ± 15 (24-77) 50 ± 15 (24 - 77) 40 ± 13 (26 - 75) .007

Hemodynamic Values Reached During Vasodilator Testing in Acute Responders

Values are mean ± SD (range).
*Comparison between long-term CCB responders and CCB failure groups (unpaired Student t or x 2 test, as appropriate.
CCB = calcium channel blockers; CO = cardiac output; NO = nitric oxide; PAP = pulmonary arterial pressure; PVR = pulmonary vascular resistance; WU = Wood units
Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Table 2.  

Acute NO/Epoprostenol Responders Group (n = 70) Long-term CCB Responders Group (n = 38) CCB Failure Group (n = 32) P*
Drug tested (NO:epoprostenol) (n) 57:13 33:5 24:8 .2
Mean PAP reached during acute vasodilator testing (mm Hg) 38 ± 11 (18-65) 33 ± 8 (18-50) 46 ± 10 (18-65) < .001
Fall in mean PAP during acute vasodilator testing (mm Hg) 19 ± 7 (10-36) 21 ± 7 (10 - 36) 16 ± 6 (10 - 33) .006
Percent fall in mean PAP 33 ± 11 (20-59) 39 ± 11 (20 - 59) 26 ± 7 (20 - 49) < .001
PVR reached during acute vasodilator testing (WU) 6.6 ± 3.4 (1.1 - 17.4) 5.2 ± 2.7 (1.1 - 13.1) 8.6 ± 3.3 (1.1 - 17.4) < .001
Fall in PVR during acute vasodilator testing (WU) 5.6 ± 3.3 (1.6 - 16.7) 5.1 ± 3.1 (1.7 - 15.4) 6.2 ± 3.4 (1.6 -16.7) .16
Percent fall in PVR 45 ± 15 (24-77) 50 ± 15 (24 - 77) 40 ± 13 (26 - 75) .007

Hemodynamic Values Reached During Vasodilator Testing in Acute Responders

Values are mean ± SD (range).
*Comparison between long-term CCB responders and CCB failure groups (unpaired Student t or x 2 test, as appropriate.
CCB = calcium channel blockers; CO = cardiac output; NO = nitric oxide; PAP = pulmonary arterial pressure; PVR = pulmonary vascular resistance; WU = Wood units
Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Table 3.  

Used with permission from: Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.

The Role of Calcium Channel Blockers in Pulmonary Arterial Hypertension: Improved Criteria for Predicting Long-term Response to CCBs

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Improved Criteria for Predicting Long-term Response to CCBs

In 2005, Sitbon and colleagues[19] published a large retrospective study of 557 patients with IPAH who underwent acute vasodilator testing with either epoprostenol (28%) or NO (72%), which helped to define criteria more predictive of long-term responsiveness to CCB therapy. Prospectively, the authors used the criteria by Rich and colleagues of a decrease in both mPAP and PVR of > 20% to define a significant acute response. They reported that 70 patients (12.6%) exhibited a vasodilator response with either epoprostenol or NO, with a mean decrease in mPAP of 33 ± 11% and in PVR of 45 ± 15%. This group of acute responders was then treated chronically with CCBs. Only 38 patients -- 54% of the acute responders and 6.8% of the entire patient population -- demonstrated a long-term response to CCBs, which was defined as improvement to functional class I or II with sustained hemodynamic improvement after 1 year of therapy. The other 32 acute responders but long-term CCB nonresponders were treated with an average dose of 144 ± 68 mg of nifedipine or 431 ± 174 mg of diltiazem, somewhat lower than the average doses reported in the study by Rich and colleagues.[10] However, the 38 long-term responders were treated with similar doses of cardizem or nifedipine, which makes inadequate dosing of CCBs an unlikely explanation for the substantially lower long-term response rate in this study.

When Sitbon and colleagues compared the clinical and hemodynamic characteristics of the long-term CCB responders with those of the nonresponders, they found significant baseline differences in hemodynamics, severity of disease (as assessed by functional class), and 6-minute walk distance (See Table 1 and Table 2 ). Additionally, the decrease in mPAP and PVR at the time of acute vasodilator testing, as a percent fall from baseline, in the 38 long-term responders was significantly greater; P < .001 and P = .007, respectively ( Table 2 ). Finally, there was a significant survival difference between long-term CCB responders and nonresponders; P = .0007 (see Figure 6). In a multivariate analysis, only baseline mixed-venous saturation and PVR reached during acute vasodilator testing were associated with improvement with CCB treatment.

Figure 6.

Enlarge

Kaplan-Meier estimates in the 57 of 70 acute responder patients who survived after 1 year onward on calcium channel blocker (CCB) therapy. The number of patients included in the long-term CCB failure subgroup was only 19 of 32, with the 13 remaining patients having died (n = 6), been transplanted (n = 4), or been lost to follow-up (n = 3, considered "dead" in the analysis) within the first year. The difference between the group of long-term CCB responders (solid line) and that of patients who failed on CCB (dashed line) was highly significant (P = .0007 by Cox-Mantel log-rank test).
Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Recent guidelines, based on the findings of Sitbon and colleagues and on expert opinion, have been published by the European Society of Cardiology (ESC) proposing that long-term CCB responders can be identified by a decrease in mPAP of at least 10 mm Hg to mPAP < 40 mm Hg along with a normal CO.[19,20] However, 6 of the 38 long-term CCB responders in the study by Sitbon and colleagues did not meet the new criteria, and 10 of 32 CCB nonresponders achieved mPAP < 40 mm Hg during acute testing, although not all of them had a decrease of > 10 mm Hg. Therefore, although there are now published guidelines for an acute vasodilator response predictive of long-term CCB response, these are not absolute criteria. There are additional individual factors that contribute to the decision to treat or not treat a PAH patient with CCBs.