Although intravenous adenosine is recommended for acute vasodilator testing in patients with pulmonary hypertension, long-term outcomes in acute responders treated with calcium channel blockers (CCBs) who are identified by adenosine remain unknown. In this study, the value of adenosine for identifying long-term responders to CCBs was investigated in patients with idiopathic pulmonary arterial hypertension (IPAH). All acute responders were subsequently treated with high-dose CCB monotherapy, and 6-minute walk distances, hemodynamic data, and World Health Organization functional classifications were followed. Nine of 104 patients exhibited an acute response with intravenous adenosine (8.7%, 95% confidence interval 3.2 to 14.2). After 12 months of follow-up, all acute responders were still alive; however, only 6 patients showed sustained hemodynamic improvement (5.8%, 95% confidence interval 2 to 13). Three patients had failed CCB monotherapy and bosentan was added to their treatment. Mean tolerated dose of intravenous adenosine was 142 ± 49 μg/kg/min. No life-threatening adverse events were observed and only 2 patients of the nonresponders exhibited a 20% decrease in mean systemic arterial pressure. In nonresponders, 1- and 3-year survival rates were 89% and 75%, respectively. In conclusion, acute vasodilator testing with intravenous adenosine was safe and able to screen responders to CCB therapy in patients with IPAH. Long-term CCB responders accounted for about 5.8% of patients with IPAH.
It is known that a near normalization of pulmonary hemodynamics in response to acute vasodilator testing is needed to warrant consideration of long-term calcium channel blocker (CCB) therapy. Intravenous epoprostenol or adenosine and inhaled nitric oxide are the most widely used and extensively studied agents for this purpose and are recommended in patients with idiopathic pulmonary arterial hypertension (IPAH) by current guidelines. Adenosine has been used successfully for >20 years because it is an endogenous nucleoside with a potent vasodilator effect and is readily available and inexpensive. However, the maximal dose of adenosine recommended in the guidelines is likely to be too high in daily practice, and the long-term outcome of its use for identifying patients likely to respond to CCB therapy remains incomplete. The aims of this study were to (1) determine the proportion of patients with IPAH who respond to acute vasodilator testing with intravenous adenosine and long-term CCB monotherapy; (2) determine whether an acute response to adenosine could predict a long-term beneficial effect with CCB therapy in patients with IPAH; and (3) assess the clinical status, hemodynamic responses, and outcomes of long-term CCB therapy in acute responders to adenosine.
Methods
This study was performed at 2 university medical centers in China from October 2006 to January 2009. One hundred four consecutive patients with newly diagnosed IPAH and World Health Organization (WHO) functional classes I to III were enrolled according to standardized diagnostic and management approaches for PAH. The follow-up period for analysis of patient data was continued until April 2011. The study was conducted in accordance with the Declaration of Helsinki and was approved by ethics committee at each study center. Written informed consent was obtained from all patients when they were recruited to the study.
PAH was defined by mean pulmonary arterial pressure (mPAP) at rest >25 mm Hg during right heart catheterization, mean pulmonary capillary wedge pressure ≤15 mm Hg, and pulmonary vascular resistance (PVR) >3 Wood units. Exclusion criteria were (1) presence of any other medical conditions in patients with WHO class I PAH; (2) patients with WHO classes II, III, IV, and V and pulmonary hypertension; and (3) treatment with PAH-specific drugs such as bosentan, iloprost, sildenafil/vardenafil, aminophylline, or dipyridamole within 4 weeks before the study.
All patients underwent complete baseline hemodynamic evaluations after discontinuation of any previously administered vasodilator agents for ≥48 hours using standard right heart catheterization techniques. All evaluations were conducted in a cardiac catheterization laboratory by standard methods. Hemodynamic parameters measured at baseline and after administration of vasodilators included mean right atrial pressure, mPAP, pulmonary capillary wedge pressure, and cardiac output, which were determined in triplicate using a thermodilution technique (Edwards Lifesciences World Trade Co., Ltd. Irvine, California). The Fick method was used to measure cardiac output in patients with severe tricuspid insufficiency. Cardiac index was calculated as cardiac output divided by body surface area (square meters). PVR was determined as (mPAP minus mean pulmonary capillary wedge pressure)/cardiac output and was expressed as Wood units. Heart rate and transcutaneous arterial oxygen saturation were monitored continuously during the procedure.
After baseline hemodynamic data had been recorded, adenosine (Ever Bright Pharmaceutical Company, Shenyang, China) was administered by continuous intravenous infusion at a dose of 50 μg/kg/min through a pulmonary catheter every 2 minutes, up to a maximal dose of 250 to 350 μg/kg/min according to current guidelines. Hemodynamic parameters and blood gases were monitored during adenosine administration. Infusion was terminated if there was an increase in heart rate of >50 beats/min or a decrease of 20% in mean systemic arterial pressure from baseline or when other intolerable symptoms such as dyspnea or chest discomfort were encountered. All adverse events observed were recorded. A positive response was defined as a decrease in mPAP of ≥10 mm Hg up to a maximum of ≤40 mm Hg, with an increased or unchanged cardiac output. All measurements were performed at constant room temperature with patients at rest in the supine position.
Long-term oral CCB therapy was initiated only in patients who displayed significant acute pulmonary vasoreactivity, as defined earlier. The drug used was diltiazem, which was initiated at an oral dosage of 30 mg 3 times/day, after which dosages were increased up to 120 to 160 mg 4 times/day if patients did not exhibit severe adverse effects. Repeated right heart catheterization was performed after ≥6 months of CCB treatment and patients’ clinical features and hemodynamic parameters were re-evaluated.
Long-term responders to CCB therapy were defined as those who had marked hemodynamic improvement and were in WHO functional class I or II after ≥6 months on CCB therapy without the addition of PAH-specific therapies. Other treatments such as diuretics, warfarin, and digoxin that patients had previously received were continued.
Independent t test and chi-square test were employed to compare differences between mean baseline values and rates for acute responders and acute nonresponders. One-way analysis of variance with repeated measurements was performed for functional and hemodynamic values obtained at baseline, during vasodilator testing, and after long-term CCB therapy. Multiple comparisons were made when the F value was statistically significant. Survival curves were derived using the Kaplan–Meier method and analyzed with log-rank test. A 2-tailed p value <0.05 was considered to indicate a statistically significant difference. Statistical analysis was performed using SPSS 14.0 (SPSS, Inc., Chicago, Illinois).
Results
In total 104 patients with IPAH (73 women, 31 men) were enrolled in this study including 4 with familial PAH. Patients’ clinical characteristics and baseline hemodynamic parameters are listed in Table 1 . All patients had severe hemodynamic features including markedly increased mPAP, mean right atrial pressure, and PVR and a decreased cardiac index.
| Variable | Acute Responders | p Value ⁎ | ||
|---|---|---|---|---|
| All Patients (n = 104) | Yes(n = 9) | No(n = 95) | ||
| Age (years) | 32 (28–42) | 28 (24–32) | 32 (28–44) | 0.02 |
| Women | 73 (70%) | 7 (78%) | 66 (69%) | 0.4 |
| Height (cm) | 162 (159–167) | 162 (160–165) | 162 (159–167) | 0.9 |
| Weight (kg) | 56 (51–65) | 56 (54–65) | 56 (50–66) | 0.4 |
| Body mass index (kg/m 2 ) | 22 (20–24) | 22 (20–25) | 22 (20–24) | 0.2 |
| World Health Organization functional class | <0.001 | |||
| I | 2 (2%) | 0 | 2 (2%) | |
| II | 43 (41%) | 8 (89%) | 35 (37%) | |
| III | 59 (57%) | 1 (11%) | 58 (61%) | |
| Onset to diagnosis (months) | 50 (10–91) | 38 (8–86) | 61 (12–96) | 0.009 |
| 6-Minute walking distance (meters) † | 380 (317–450) | 453 (420–496) | 376 (315–450) | <0.001 |
| Heart rate (beats/min) | 86 (76–96) | 75 (67–78) | 85 (76–96) | 0.09 |
| Mean right atrial pressure (mm Hg) | 6 (2–10) | 2 (1–6) | 6 (2–10) | 0.008 |
| Mean pulmonary arterial pressure (mm Hg) | 63 (52–70) | 45 (41–54) | 64 (52–72) | <0.001 |
| Mean pulmonary capillary wedge pressure (mm Hg) | 7 (4–10) | 7 (4–12) | 8 (5–10) | 0.8 |
| Cardiac index (L/min/m 2 ) | 2.0 (1.7–2.5) | 3.3 (2.5–3.8) | 2.1 (1.8–2.5) | 0.01 |
| Pulmonary vascular resistance (Wood units) | 17 (12–23) | 7 (6–9) | 18 (12–23) | <0.001 |
| Mixed venous blood oxygen saturation (%) | 61 (53–65) | 73 (69–74) | 59 (54–67) | <0.001 |
⁎ Comparison between acute responders and nonacute responders.
† Six-minute walking distance was successfully measured in 102 patients of the total population and 93 nonacute responders.
All patients with IPAH underwent acute testing with intravenous adenosine, 95 of whom (91.3%, 95% confidence interval [CI] 89.9 to 96.0) did not respond to the acute vasodilator challenge and did not receive CCB therapy. The remaining 9 patients (8.7%, 95% CI 3.2 to 14.2) who responded acutely to adenosine received CCB monotherapy. Differences in baseline clinical characteristics and hemodynamic variables between acute responders and nonresponders to adenosine are listed in Table 1 . Compared to nonresponders, acute responders were younger and had a better WHO functional classification (ratio 8 to 1 for class I vs 37 to 58 for class II/III, respectively, p <0.001).
Hemodynamic findings during the acute vasodilator challenge with adenosine are presented in Table 2 . The 9 patients (all with IPAH) who responded to the adenosine challenge exhibited a significant decrease in mPAP (34 ± 18%, range 26 to 43) and PVR (54 ± 44%, range 40 to 64). The 95 patients who did not respond significantly to adenosine exhibited only a slight decrease in mPAP (7 ± 6%, range 6 to 9) and PVR (7 ± 2%, range 6 to 21). Mean dose of adenosine in the 9 patients who showed a response was 78 ± 23 μg/kg/min (range 50 to 100), and mean maximum tolerated infusion rate was 100 ± 31 μg/kg/min (range 50 to 125).
| Acute Responders (n = 9) | Nonacute Responders (n = 95) | |||
|---|---|---|---|---|
| Variable | Baseline | Adenosine | Baseline | Adenosine |
| Heart rate (beats/min) | 75 (67–78) | 87 (70–92) | 85 (76–96) | 90 (81–102) § |
| Mean systemic arterial pressure (mm Hg) | 82 (79–89) | 76 (72–86) | 85 (79–96) | 81 (73–89) |
| Mean pulmonary arterial pressure (mm Hg) | 45 (41–54) | 30 (29–36) † | 64 (52–72) | 60 (50–69) |
| Mean right atrial pressure (mm Hg) | 2 (1–6) | 2 (2–6) | 6 (2–10) | 7 (3–11) |
| Mean pulmonary capillary wedge pressure (mm Hg) | 7 (4–12) | 12 (6–13) | 8 (5–10) | 9 (7–12) |
| Cardiac index (L/min/m 2 ) | 3.3 (2.5–3.8) | 4.4 (2.8–4.8) † | 2.1 (1.8–2.5) | 2.4 (1.9–3.0) |
| Pulmonary vascular resistance (Wood units) | 7 (6–9) | 3 (2–5) † | 18 (12–23) | 17 (9–19) |
| Systemic vascular resistance (Wood units) | 16 (13–17) | 11 (10–13) ⁎ | 24 (20–29) | 19 (14–24) ‡ |
| Arterial oxygen saturation (%) | 95 (93–97) | 96 (95–98) | 95 (92–96) | 95 (93–97) |
| Mixed venous blood oxygen saturation (%) | 73 (69–74) | 76 (72–83) | 59 (54–67) | 65 (58–73) |
† p <0.01, comparison between baseline and adenosine in acute responders.
§ p <0.01, comparison between baseline and adenosine in nonacute responders.
Maximum tolerated dose of adenosine varied from 50 to 325 μg/kg/min. Five patients required the adenosine infusion to be stopped at a dose of 50 μg/kg/min within 5 minutes, but the remainder were able to tolerate higher dosages. Forty-nine patients (47%) developed adverse events during infusion. Of nonacute responders, 48 patients (51%) developed adverse events and 14 (15%) developed ≥2 adverse events. These adverse effects often occurred about 3 to 5 minutes after the initiation of adenosine infusion and disappeared within 2 to 3 minutes after termination of the infusion (except for 1 patient who had a mild headache that lasted for 10 minutes after the infusion was stopped). The most common adverse effects included headache, chest oppression, palpitations, cutaneous flushing, abdominal pain, and anxiety; 2 patients exhibited a 20% decrease in mean systemic arterial pressure. Of acute responders, 1 patient (11%) developed a mild headache, but the other 8 did not complain of any discomfort.
No serious adverse events such as prolonged severe hypotension, bronchospasm, acute right heart failure, or death were observed during the study.
Long-term high-dose CCB therapy with diltiazem (mean dosage 440 ± 120 mg/day, range 360 to 720) was restricted to the 9 acute responders. As presented in Table 3 , 6 patients (67%) had a sustained major vasodilator effect after 12 ± 5 months (range 6 to 19) with CCB treatment. The 3 patients who did not respond to long-term CCB treatment had the oral endothelin receptor antagonist bosentan added to their treatment. Long-term CCB responders accounted for 67% of acute responders to adenosine and 5.8% (95% CI 2 to 13) of all patients with IPAH. At the last follow-up visit (after 47 ± 4 months, range 39 to 54), the 6 long-term CCB responders displayed sustained improvement in hemodynamic parameters (presented in Table 3 ).
| Patient Number | Age (years)/Sex | Height (cm) | Weight (kg) | Follow-Up (months) | Diltiazem Dose (mg/day) | WHO Functional Class | 6MWD (meters) | mPAP (mm Hg) | PVR (Wood units) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Follow-Up | Baseline | Follow-Up | Baseline | Follow-Up | Baseline | Acute Vasodilator Testing | Follow-Up | Baseline | Acute Vasodilator Testing | Follow-Up | |||||
| 1 | 19/F | 164 | 62 | 42 | 180 | 480 | 2 | 1 | 570 | 610 | 42 | 17 | 29 | 8.9 | 1.9 | 3.9 |
| 2 | 24/F | 158 | 68 | 39 | 180 | 640 | 2 | 1 | 405 | 560 | 41 | 29 | 22 | 3.3 | 1.7 | 1.1 |
| 3 | 24/F | 153 | 56 | 50 | 120 | 480 | 2 | 2 | 510 | 590 | 37 | 23 | 32 | 7.0 | 3.5 | 3.5 |
| 4 | 28/F | 165 | 54 | 42 | 120 | 480 | 2 | 1 | 482 | 512 | 51 | 36 | 39 | 7.4 | 2.4 | 4.9 |
| 5 | 28/F | 162 | 53 | 53 | 180 | Bosentan 125 mg | 2 | 4 | 453 | 318 | 59 | 38 | 127 | 15 | 5.4 | 23 |
| 6 | 28/M | 174 | 95 | 46 | 180 | Bosentan 125 mg | 3 | 4 | 360 | 342 | 45 | 30 | 65 | 6.2 | 2.8 | 10.5 |
| 7 | 32/M | 165 | 55 | 45 | 180 | Bosentan 125 mg | 2 | 4 | 420 | 460 | 54 | 34 | 65 | 12.0 | 6.7 | 15.5 |
| 8 | 36/F | 158 | 42 | 47 | 120 | 640 | 2 | 2 | 496 | 525 | 38 | 29 | 32 | 8.2 | 5.7 | 3.6 |
| 9 | 42/F | 160 | 65 | 45 | 120 | 640 | 2 | 1 | 434 | 536 | 56 | 29 | 40 | 3.3 | 1.6 | 2.4 |
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