Pulmonary Hypertension

Background
Pulmonary hypertension (PH) is defined as an elevation of the resting mean pulmonary arterial pressure ( 25 mmHg) as determined by right heart catheterization(RHC). There are several potential etiologies for elevation in mean pulmonary artery pressure in people with SCD. Chronic hemolytic anemias, including SCD, may result in pulmonary vascular changes leading to pulmonary arterial hypertension (PAH), and are placed in Group 1 of the current classification (https://www.nhlbi.nih.gov/health/health-topics/topics/pah/types.html)

This type of pulmonary hypertension may occur in up to 10 percent of those with SCA and accounts for 40 to 50 percent of cases of PH. The second most common type of PH in SCD is pulmonary venous hypertension (PVH), assigned to Group 2 in the current classification, which is associated with an elevated pulmonary capillary wedge pressure of l5 mmHg.This is often associated with left ventricular diastolic dysfunction. PH also occurs in the setting of chronic lung disease, chronic thromboembolic disease, or can be due to unclear or multiple mechanisms (Groups 3, 4, and 5 of the classification, respectively). Because these circumstances may also be present in individuals with SCD, a thorough evaluation of mechanisms and comorbidities should be undertaken if PH is found.

Initial testing for PH has been done with an echocardiography assessment to estimate pulmonary artery pressure using tricuspid regurgitant jet velocity (TRV), but diagnosis requires right heart catheterization and direct measurement of the pulmonary arterial pressure and vaso-reactivity of the vessels. Transient elevation in TRV has been observed during acute vaso-occlusive episodes in individuals with SCD, which may not reflect baseline values or present chronic PH.

The main symptoms of PH include shortness of breath during routine activity, such as climbing two flights of stairs; fatigue; lethargy; chest pain; palpitations; syncope; peripheral edema; and decreased appetite. Careful history taking is needed to distinguish symptoms related to the anemia of SCD itself from the new onset of symptoms related to the development of PH.

Observational studies show an increase in all-cause mortality for adults with SCA with an elevated TRV by echocardiography, although this association has not been found in children. In children and young adults with relatively normal renal function, only 25-30 percent of those with an elevated TRV may have an elevated pulmonary artery pressure measured by right heart catheterization. Older adults with SCA and a high TRV are more likely to have an elevated pulmonary pressure, although 40 percent of those with a high TRV will have an elevated wedge pressure suggesting left heart disease.

A commonly associated finding is renal insufficiency. The Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) study was published outside of the range of the evidence review for these guidelines and thus was not included. This study enrolled 33 subjects with SCD and PH defined by an elevated TRV of 2.7 m/sec and a 6-minute walk distance (6MWD) of 150-500 meters.47 RHC was required in the TRV 3.0 m/sec group; all subjects were randomized to sildenafil or placebo regardless of findings at RHC. This study was closed early due to an increase in serious adverse events associated with sildenafil use; estimation of results by futility analysis suggested no improvement in 6MWD would be demonstrated if the study continued. These data confirm earlier data that RHC is necessary to confirm the presence of PH and distinguish the mechanism of disease before considering therapy for PH. It is unknown if intervention for SCD (e.g., transfusion or hydroxyurea) would change the all-cause mortality associated with an elevated TRV.

Key Question

Summary of the Evidence
Two RCTs, seven observational studies, and three case reports examined the management of PAH. No clear therapeutic benefit has been shown for any pharmacotherapy for PAH in people with all types of SCD, and the overall quality of the evidence on therapy was considered very low.
The two RCTs were reported in one paper, and enrolled 26 people, blinded patients and outcome assessors to the intervention assignment, and did not report any baseline imbalances or allocation concealment. Both trials were stopped prematurely due to slow enrollment. The trials compared bosentan to placebo and showed no improvement in the 6MWD or levels of pulmonary hypertension.

The seven observational studies included more than 200 people and evaluated various aspects of PAH. Five studies examined various therapies, and two looked at mortality rates. Increased mortality was reported in all people with SCD with true PAH (55 percent vs. 21 percent 10-year mortality respectively in all people with SCD with and without PAH). The five small observational studies reported various levels of benefit from five different types of pharmacotherapy, but no consistent definition of PAH was used across these uncontrolled studies, making it difficult to compare results. The five therapies studied were bosentan, sildenafil, L-arginine, L-camitine, and hydroxyurea. Both bosentan and sildenafil were reported to increase 6MWD.

L-arginine was reported to improve pulmonary arterial function, although this was a short-term benefit. Although results from a pilot study of sildenafil suggested improved exercise capacity in pulmonary hypertension, the study was stopped early due to safety concerns and the authors cautioned that additional studies on the safety of sildenafil in this patient population were needed. L-camitine was reported to improve cardiac diastolic function, and hydroxyurea was reported to normalize elevated tricuspid regurgitant velocity (TRV), but this was not sustained long term.

Recommendations

If people with SCD have symptoms or signs suggestive of PH, refer them for echocardiography.
(Strong Recommendation;Moderate-Quality Evidence)
For people with an elevated TRV 2.5 m/sec by echocardiography, consult a provider with expertise in pulmonary hypertension to guide further assessment and management, including right heart catheterization, and consideration of PH therapy.
(Consensus-Panel Expertise)

Dr. Rob’s Form and Function for your use