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Hypertension

Hypertension or high blood pressure is a medical condition where the blood pressure is chronically elevated. While it is formally called arterial hypertension, the word "hypertension" without a qualifier usually refers to arterial hypertension. more...

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Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure.

Definition

Blood pressure is a continuous variable, and risks of various adverse outcomes rise with it. A blood pressure of less than 120/80 mmHg is defined as "normal" in adults. Hypertension is usually diagnosed on finding blood pressure of 140/90 mmHg or above, measured on both arms on three occasions over a few weeks.

Recently, the JNC VII (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) has defined blood pressure 120/80 mmHg to 140/90 mmHg as "prehypertension". Prehypertension is not a disease category. Rather, it is a designation chosen to identify individuals at high risk of developing hypertension (JNC VII).

In patients with diabetes mellitus or kidney disease studies have shown that blood pressure over 130/80 mmHg should be considered a risk factor and may warrant treatment.

Etiology

Essential hypertension

  • Age. Over time, the number of collagen fibres in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross-sectional area in systole, and so a raised mean arterial blood pressure.
  • High salt intake
  • Sedentary lifestyle
  • Tobacco smoking
  • Alcohol abuse
  • High levels of saturated fat in the diet
  • Obesity. In obese subjects, losing a kilogram of mass generally reduces blood pressure by 2 mmHg.
  • Stress
  • Low birth-weight
  • Diabetes mellitus
  • Various genetic causes

Secondary hypertension

While most forms of hypertension have no known underlying cause (and are thus known as "essential hypertension" or "primary hypertension"), in about 5% of the cases, there is a known cause, and thus the hypertension is secondary hypertension.

Pathophysiology

The mechanisms behind the factors associated with inessential hypertension are generally fully understood, and are outlined at secondary hypertension. However, those associated with essential hypertension are far less understood. What is known is that cardiac output is raised early in the disease course, with total peripheral resistance normal; over time cardiac output drops to normal levels but TPR is increased. Three theories have been proposed to explain this:

  • Inability of the kidneys to excrete sodium, resulting in natriuretic factor (note: the existence of this substance is theoretical) being secreted to promote salt excretion with the side-effect of raising total peripheral resistance.
  • An overactive renin / angiotension system leads to vasoconstriction and retention of sodium and water. The increase in blood volume leads to hypertension.
  • An overactive sympathetic nervous system, leading to increased stress responses.

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Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension
From CHEST, 10/1/05 by Marius M. Hoeper

Study objectives: We performed an open-label multicenter study to evaluate the safety and efficacy of the dual endothelin receptor antagonist bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).

Patients: Nineteen patients with inoperable CTEPH were enrolled.

Measurements: The primary end point was a change in pulmonary vascular resistance (PVR). Secondary end points included 6-min walk test, peak oxygen uptake (V[O.sub.2]), New York Heart Association functional class, serum levels of N-terminal-pro brain natriuretic peptide (NT-pro-BNP), and various other hemodynamic parameters.

Results: After 3 months of treatment with bosentan, PVR decreased from 914 [+ or -] 329 to 611 [+ or -] 220 dynexsx[cm.sup.-5] (p < 0.001). Functional class and peak V[O.sub.2] remained unchanged, but 6-min walk distance increased from 340 [+ or -] 102 to 413 [+ or -] 130 m (p = 0.009), and serum NT-pro BNP levels improved from 2,895 [+ or -] 2,620 to 2,179 [+ or -] 2,301 (p = 0.027). One patient died, presumably from influenza A infection, and another patient experienced progressive fluid retention despite reduction of PVR. Other than that, treatment was well tolerated by all patients.

Conclusions: This open-label pilot trial suggests that bosentan may offer a therapeutic option for patients with inoperable CTEPH. Randomized controlled trials are warranted to confirm these findings.

Key words: hypertension, pulmonary; thromboembolism, endothelin

Abbreviations: CI = cardiac index; CPET = cardiopulmonary exercise testing; CTEPH = chronic thromboembolic pulmonary hypertension; INR = international normalized ratio; NT-pro-BNP = N terminal-pro brain natriuretic peptide; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PAPm = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PEA = pulmonary endarterectomy; PVR = pulmonary vascular resistance; RAP = fight atrial pressure; Sv[O.sub.]2 = mixed venous oxygen saturation; V[O.sub.2] = oxygen uptake

**********

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in up to 3.8% of patients who survive acute pulmonary embolism. (1) In addition, CTEPH is often identified during the diagnostic workup of patients with unexplained pulmonary hypertension, many of whom lacking a history suggestive of previous episodes of pulmonary embolism. Thus, the true incidence of CTEPH is unknown, but the entity has become a leading diagnosis in major referral centers for patients with severe pulmonary hypertension worldwide.

Left untreated, the prognosis of CTEPH is poor, and the 5-year mortality has been reported to approach 90% in patients when the mean pulmonary artery pressure (PAPm) is > 30 mm Hg. (2) Surgical pulmonary endarterectomy (PEA) is the procedure of choice for patients with CTEPH, offering a chance for near-normalization of hemodynamics, exercise tolerance, and quality of life, and a 5-year-survival rate of 75 to 80%. (3-6) However, some patients may not be candidates for surgery because of predominant involvement of peripheral pulmonary arteries. In addition, an unknown number of operated patients may exhibit persistent or recurrent pulmonary hypertension not amenable to repeated surgery. In these patients, a "secondary" vasculopathy of peripheral pulmonary vessels is involved, with histologic features resembling those seen in pulmonary arterial hypertension (PAH), (7) and they might therefore benefit from medical treatment with drugs that have been shown to be effective in PAH. Supporting this hypothesis, uncontrolled studies (8-10) suggest that epoprostenol and sildenafil may improve hemodynamics and exercise capacity in patients with CTEPH.

Bosentan, a dual endothelin receptor antagonist, has beneficial effects in several types of PAH. (11) Its role in the treatment of CTEPH has not yet been studied. We therefore conducted the present open-label pilot trial to assess whether there is any therapeutic potential of bosentan in patients with inoperable CTEPH.

MATERIALS AND METHODS

Patient Selection

In order to ensure diagnostic accuracy and to prevent inclusion of patients with operable disease, this study was carried out at the three largest referral centers for surgical treatment of CTEPH in Germany. All patients underwent standardized assessment at the centers including ventilation/perfusion scanning, helical CT of the chest, and pulmonary angiography. The final decision to classify the patient as inoperable was made together with the surgeon in charge of the PEA program. Patients who underwent PEA were followed up in the centers in 3- to 6-month intervals by echocardiography and clinical assessment. In patients with symptoms or signs of persistent pulmonary hypertension after PEA, a diagnostic right-heart catheterization was performed, and a repeated diagnostic workup was started when the patients were considered candidates for repeated surgery.

Inclusion criteria for this study were as follows: (1) CTEPH judged as inoperable because of peripheral location of vascular obliteration by an experienced surgeon; (2) persistent or recurrent pulmonary hypertension after PEA with no evidence of recurrent thromboembolism and not amenable to repeated surgery; and (3) hemodynamic evaluation showing precapillary pulmonary hypertension (pulmonary capillary wedge pressure [PCWP] < 15 mm Hg), with a PAPm > 35 mm Hg and a pulmonary vascular resistance (PVR) > 500 dynesxsx[cm.sup.-5]. Exclusion criteria were as follows: (1) patients with other forms of pulmonary hypertension; (2) patients with CTEPH who had proximal occlusion of pulmonary arteries deemed operable by an experienced surgeon, but who declined operation or who were not considered operable due to other medical reasons; (3) pregnant or nursing women or women with child-bearing potential who did not use an acceptable method of contraception; and (4) patients with aspartate aminotransferase and/or alanine aminotransferase levels above three times the upper limit of normal. The study protocol was approved by the ethics committees of the participating centers, and all patients gave written informed consent.

Treatment and Follow-up

Prior to bosentan treatment, all patients underwent a physical examination, right-heart catheterization, 6-min walk testing, and cardiopulmonary exercise testing (CPET). In addition, blood samples were obtained for assessment of liver function, anticoagulation (international normalized ratio [INR]), troponin-T, and N-terminal-pro-brain natriuretic peptide [NT-pro-BNP]). Patients received treatment with bosentan, starting with 62.5 mg bid for 4 weeks and continuing with 125 mg bid for additional 8 weeks. The patients were seen at the study centers every 4 weeks for safety evaluation including assessment of anticoagulation (INR), transaminases, and 6-min walk distances. In addition, INR was monitored at least once a week during the first 6 weeks of the study to ensure adequate anticoagulation. The final evaluation was made after 12 weeks of bosentan treatment and consisted of the same tests as performed at baseline.

Safety and Efficacy End Points

The primary end point was the change from baseline in PVR after 12 weeks of bosentan treatment. Secondary end points (all after 12 weeks of treatment) were as follows: change from baseline in PAPm, cardiac index (CI), right atrial pressure (RAP), and mixed venous oxygen saturation (Sv[O.sub.2]), exercise capacity (6-min walk-test), peak oxygen uptake (V[O.sub.2]), peak oxygen pulse, ventilatory efficacy for carbon dioxide at the anaerobic threshold, Borg dyspnea index (assessed after the 6-min walk test), and World Health Organization functional class of pulmonary hypertension.

Statistics

Analysis was of patients treated per protocol. All values are given as mean [+ or -] SD. A Student paired t test (two sided) was used to compare variables at baseline and after 3 months of treatment; p < 0.05 was considered statistically significant.

RESULTS

Between September 2003 and June 2004, 19 patients were enrolled into this study. Four patients had persistent/recurrent pulmonary hypertension after previous PEA (1.5 years, 4 years, 5 years, and 6 years after surgery, respectively); the others had nonoperable CTEPH. The interval between diagnosis of CTEPH and study entry was > 3 months in all patients and was > 12 months in 10 patients. All patients had received adequate treatment with oral anticoagulants since diagnosis. Demographics, clinical characteristics, and hemodynamics are depicted in Table 1. Eighteen patients completed this study; 1 patient died 6 weeks after the introduction of bosentan. This patient was a 41-year-old woman who underwent PEA 6 years before entering this study. After operation, she had persistent and progressive pulmonary hypertension and was in New York Heart Association (NYHA) functional class IV when she entered this study. After 4 weeks of bosentan treatment, her 6-min walk test had improved from 66 to 198 m. However, 2 weeks later, a febrile illness and symptoms suggestive of influenza A infection developed (an influenza A epidemic was sweeping over Germany during that time). The patient died suddenly 2 days after the onset of fever. Death was considered unrelated to medical treatment by the investigators and the hospital ethics committee. This patient was excluded from all further analysis.

Hemodynamic Responses

Results of cardiac catheterization at baseline and after 3 months of bosentan treatment are shown in Table 2 and Figure 1. PVR declined from 914 [+ or -] 329 to 611 [+ or -] 220 dynexsx[cm.sup.-5] (p < 0.001). PAPm fell from 48 [+ or -] 8 to 42 [+ or -] 8 mm Hg (p = 0.004), and cardiac output rose from 4.0 [+ or -] 1.1 to 4.7 [+ or -] 1.3 L/rain (p < 0.001). Stroke volume increased from 54 [+ or -] 15 to 64 [+ or -] 21 mL (p = 0.009), and the Sv[O.sub.2] increased from 59 [+ or -] 8 to 64 [+ or -] 8% (p = 0.005). There were no significant changes in heart rate, RAP, PCWP, and systemic arterial pressure.

[FIGURE 1 OMITTED]

Functional Assessment, 6-min Walk Distance, and CPET

At baseline, 2 patients were in NYHA functional class II, 14 patients were in NYHA class III, and 2 patients were in NYHA class IV. After 3 months of bosentan treatment, one patient had progressed from NYHA functional class III to functional class IV, three patients had improved from functional class III to functional class II, and one patient improved from class IV to class III; the remaining patients were assigned the same functional class as at baseline.

As shown in Figure 2, the 6-min walk distance increased significantly from 340 [+ or -] 102 to 413 [+ or -] 130 m (p = 0.009). The Borg dyspnea score remained unchanged (5.7 [+ or -] 2.0 at baseline vs 5.3 [+ or -] 2.4 after 3 months, p = 0.19).

[FIGURE 2 OMITTED]

Results from CPET were nonconclusive, which may be partly due to the fact that complete sets of pretreatment and posttreatment measurements were obtained only from 12 patients. Missing values were due to either technical reasons or the incapability of some patients to perform CPET. Analysis of the 12 patients who completed the procedure revealed a nonsignificant increase in peak V[O.sub.2] from 14.1 [+ or -] 3.2 to 15.1 [+ or -] 3.8 mL/min/kg (p = 0.17) and an increase in oxygen pulse from 8.6 [+ or -] 3.1 to 9.5 [+ or -] 3.1 mL that was of borderline significance (p = 0.058). Ventilatory efficacy for carbon dioxide at the anaerobic threshold declined from 52 [+ or -] 10 to 47 [+ or -] 7 (p = 0.064), suggesting a trend toward improved pulmonary perfusion during exercise.

Laboratory Values

During bosentan treatment, plasma levels of alanine aminotransferase and aspartate aminotransferase were above the upper level of normal in four patients (22%) but remained below the mark of three times the upper limit of normal in all patients. There were no dose adjustments or treatment interruptions due to liver dysfunction.

In order to maintain INR values in the target range between 2.5 and 3.0, the dose of phenprocoumon (and oral anticoagulant widely used in Germany instead of warfarin) had to be increased between 25% and 100% from baseline, which is consistent with the known stimulatory effects of bosentan on cytochrome oxidase-dependent metabolic pathways. (12,13) Serum levels of troponin T were below the detection limit of < 0.01 [micro]g/L in all patients at all times during the study.

Serum levels of NT-pro-BNP were elevated in all patients at baseline (mean [+ or -] SD, 2,895 [+ or -] 2,620 ng/L; range, 536 to 11,114 ng/L; upper limit of normal, 200 ng/L). After 3 months of bosentan treatment, NT-pro-BNP levels decreased to 2,179 [+ or -] 2,301 ng/L (p = 0.027).

Side Effects and Adverse Events

The death of one patient and elevations of transaminases have been addressed above. In addition, one patient complained about mild upper-abdominal pain after the bosentan dose was increased to 125 mg bid, which resolved completely within a few days without dose adjustment. A total of four patients experienced fluid retention, which was transient and manageable except for one patient, who had signs and symptoms of progressive right-heart failure with an increase in RAP from 10 to 24 mm Hg and a decrease in cardiac output from 3.8 to 3.2 L/min (since the PAPm also declined and the PCWP increased, the calculated PVR formally improved). In this patient, bosentan treatment was stopped after 3 months. Other than that, no adverse events were observed.

DISCUSSION

This open-label pilot trial, despite limited by its relatively small sample size and its uncontrolled design, shows that the dual endothelin receptor antagonist bosentan may have beneficial effects in selected patients with inoperable CTEPH. On first glance, it may seem counterintuitive to use a vasoactive treatment in a disease that is characterized by mechanical obstruction of pulmonary vessels. However, several lines of evidence suggest that, after the initializing event of single, multiple, or recurrent pulmonary embolism, vascular remodeling may ensue with morphologic changes resembling those seen in PAH. (4,14) As time elapses, these secondary changes may have a more potent impact on the PVR than the original thromboembolic events. Some degree of pulmonary vasoreactivity may be preserved in patients with CTEPH,is and preliminary observations (8-l0) suggest that IV epoprostenol and sildenafil may yield beneficial hemodynamic and clinical effects in selected CTEPH patients.

Plasma levels of big-endothelin-1, the precursor of endothelin-1, are increased in patients with CTEPH compared to control subjects. (16) In addition, selective upregulation of endothelin B receptors has been demonstrated in pulmonary arterial smooth-muscle cells of patients with this disease. (16) These data provide a rationale for the use of dual endothelin receptor antagonists as potential treatments for CTEPH.

Almost all of our patients showed substantial hemodynamic improvement with bosentan treatment, but the functional response was not uniform, with the changes in 6-min walk distance ranging between -54 m and + 407 m. The observation period of 3 months might have been simply too short for some patients to derive substantial clinical benefit. The mean increase in 6-min walk distance was + 73 [+ or -] 102 m, but the median change was only + 42 m, suggesting that many patients showed just mild functional improvement while a few patients had substantial responses (a fact that is clearly visible in Fig 2). The clinical response to bosentan in patients with CTEPH appears to be highly variable, and it will be a task for future clinical trials to find out which patients among the CTEPH population will gain the highest benefit from medical treatment. Perhaps vasoreactivity testing might be a helpful tool, but this remains to be investigated.

Although the comparison of different clinical trials has obvious limitations, the observed effects of bosentan in CTEPH are strikingly similar to the results reported with the phosphodiesterase-5-inhibitor sildenafil in a similar patient population. (10) Ghofrani et al (10) treated 12 patients with inoperable CTEPH over a 6-month period with sildenafil and found an increase in mean 6-min walk distance from 312 m at baseline to 366 m at the end of the observation period (+ 17%), which is comparable to the increase from 340 to 413 m that we observed with bosentan treatment (+ 21%). The change in PVR (-30% with sildenafil treatment and -33% with bosentan treatment) was almost identical in both studies. It is impossible to judge by the present data whether any of these drugs will turn out to have superior effects in CTEPH, and both treatment strategies require more extensive long-term evaluation in controlled clinical trials, ideally alone as well as in combination. (17)

The present study was restricted to patients with predominant peripheral vascular involvement precluding successful desobliteration according to the judgement of an experienced surgeon. However, experiences with epoprostenol suggest that medical treatment may also be temporarily used in patients with operable disease to obtain hemodynamic improvement prior to surgery. (8,9) Thus, several subgroups of patients with CTEPH may be candidates for medical treatment. However, with the perspective of medical treatment becoming available for treatment of CTEPH, there is also the potential caveat that physicians may use medical remedies in patients with operable disease. PEA, when performed at an experienced center, offers the chance for substantial improvement in physical capacity and quality of life, as well as for near-normalization of hemodynamics, longevity, and even cure. (5) However, PEA is a high-risk procedure with mortality rates between 4.4% and 10.9% in experienced centers, and surgery may not be the best therapeutic option for every patient. (3,5) Effective medical treatments may be used in the preoperative period to improve hemodynamics, right-heart function and, possibly, postoperative outcome, but also as an alternative treatment for patients who are less than optimal candidates for surgery.

The present data suggest that bosentan may offer a therapeutic option for selected patients with inoperable disease. It is warranted to conduct larger, randomized controlled trials to confirm these findings.

The present study was funded by Actelion Pharmaceuticals, the manufacturer of bosentan.

Manuscript received January 25, 2005; revision accepted April 3, 2005.

REFERENCES

(1) Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350:2257-2264

(2) Riedel M, Stanek V, Widimsky J, et al. Long-term follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81:151-158

(3) Dartevelle P, Fadel E, Mussot S, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23:637-648

(4) Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345: 1465-1472

(5) Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003; 76:1457-1462; discussion 1462-1454

(6) Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43:73S-80S

(7) Moser KM, Fedullo PF, Finkbeiner WE, et al. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation 1995; 91:741-745

(8) Nagaya N, Sasaki N, Ando M, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003; 123:338-343

(9) Bresser P, Fedullo PF, Auger WR, et al. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23:595-600

(10) Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003; 167:1139-1141

(11) Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903

(12) Weber C, Banken L, Birnboeck H, et al. Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39:847-854

(13) Murphey LM, Hood EH. Bosentan and warfarin interaction. Ann Pharmacother 2003; 37:1028-1031

(14) Chaouat A, Weitzenblum E, Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996; 9:356-363

(15) Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenfil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136:515-522

(16) Bauer M, Wilkens H, Langer F, et al. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002; 105:1034-1036

(17) Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004; 24:1007-1010

Marius M. Hoeper, MD; Thorsten Kramm, MD; Heinrike Wilkens, MD; Christine Schulze; Hans Joachim Schafers, MD; Tobias Welte, MD; and Eckhard Mayer, MD

* From the Department of Respiratory Medicine (Drs. Hoeper and Welte, and Ms. Schulze), Hannover Medical School, Hanhover; Department of Cardiovascular and Thoracic Surgery (Drs. Kramm and Mayer), University Hospital of Mainz, Mainz., and Departments of Respiratory Medicine (Dr. Wilkens) and Department of Cardiovascular and Thoracic Surgery (Dr. Schafers), University of the Saarland, Homburg, Germany.

Dr. Hoeper and Dr. Wilkens have received speaker's honorariums from Actelion Pharmaceuticals. Dr. Hoeper serves as an Advisory Board Member for Actelion Pharmaceuticals.

Correspondence to: Marius M. Hoeper, MD, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany; e-mail: hoeper.marius@mh-hannover.de

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group

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