Role of CCBs in Pulmonary Arterial Hypertension

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

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.

Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation. 1989;80:1207-1221. Abstract
McMurtry IF, Davidson AB, Reeves JT, Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res. 1976;38:99-104.
Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998;98:1400-1406. Abstract
Pollock DM, Keith TL, Highsmith RF. Endothelin receptors and calcium signaling. FASEB J. 1995;9:1196-1204. Abstract
Corbin JD. Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int J Impot Res. 2004;16(Suppl 1):S4-7. Abstract
Camerini F, Alberti E, Klugmann S, et al. Primary pulmonary hypertension: effects of nifedipine. Br Heart J. 1980;44:352-356. Abstract
Rubin LJ, Nicod P, Hillis LD, et al. Treatment of primary pulmonary hypertension with nifedipine. A hemodynamic and scintigraphic evaluation. Ann Intern Med. 1983;99:433-438. Abstract
Rich S, Brundage BH, Levy PS. The effect of vasodilator therapy on the clinical outcome of patients with primary pulmonary hypertension. Circulation. 1985;71:1191-1196.
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. Abstract
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. Abstract
Schrader BJ, Inbar S, Kaufmann L, et al. Comparison of the effects of adenosine and nifedipine in pulmonary hypertension. J Am Coll Cardiol. 1992;19:1060-1064. Abstract
Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med. 1995;151:384-389. Abstract
Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. 1998;12:265-270. Abstract
Berkenboom G, Sobolski J, Stoupel E. Failure of nifedipine treatment in primary pulmonary hypertension. Br Heart J. 1982;47:511.
Packer M. Vasodilator therapy for primary pulmonary hypertension. Limitations and hazards. Ann Intern Med. 1985;103:258-270. Abstract
Prigogine T, Waterlot Y, Gottignies P, et al. Acute nonhemodynamic pulmonary edema with nifedipine in primary pulmonary hypertension. Chest. 1991;100:563-564. Abstract
Partanen J, Nieminen MS, Luomanmaki K, et al. Death in a patient with primary pulmonary hypertension after 20 mg of nifedipine. N Engl J Med. 1993;329:812.
Badesch DB, Abman SH, Ahearn GS, et al; American College of Chest Physicians. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:35S-62S. Abstract
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. Abstract
Galie N, Torbicki A, Barst R, et al; Task Force. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004;25:2243-2278. Abstract
Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208. Abstract
Yung D, Widlitz AC, Rosenzweig EB, et al. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660-665. Abstract
Nootens M, Kaufmann E, Rich S. Short-term effectiveness of nifedipine in secondary pulmonary hypertension. Am J Cardiol. 1993;71:1475-1476. Abstract
Alpert MA, Pressly TA, Mukerji V, et al. Acute and long-term effects of nifedipine on pulmonary and systemic hemodynamics in patients with pulmonary hypertension associated with diffuse systemic sclerosis, the CREST syndrome and mixed connective tissue disease. Am J Cardiol. 1991;68:1687-1691. Abstract
Woodmansey PA, O'Toole L, Channer KS, et al. Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension. Heart. 1996;75:171-173. Abstract
Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med. 1996;335:1107-1114. Abstract

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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.