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Pollution’s Ozone May Hurt Heart (CME/CE)

Immediately before, immediately after, and the day after the two exposures, participants underwent spirometry and had blood drawn. Ambulatory ECG monitoring was done throughout a 24-hour period.

There were no reports of post-exposure symptoms among the participants.

Changes in biomarkers of inflammation included an increase of 55.7% (95% CI −5.1 to 152.9) in IL-1-beta and a rise of 10.1% (95% CI −0.75 to 22.1) in tumor necrosis factor-alpha.

Even 24 hours after the ozone exposure, blood levels of IL-1-beta were 103.8% (95% CI 32.5 to 213.9) higher than at baseline, and C-reactive protein levels were 65.4% (95% CI 8.1 to 152.9) above pre-exposure levels.

The decrease in the thrombotic marker PAI-1 remained 24 hours after exposure, giving an overall 42.7% reduction (95% CI −65.5 to −5.1).

After 24 hours, plasminogen levels had decreased by 41.5% (95% CI −67.1 to −16).

The researchers also detected a “small but significant” lengthening of the QT interval immediately following ozone exposure, a finding which they noted can increase risk for ventricular tachyarrhythmias and even sudden death.

Additionally, spirometric measures showed changes including a 10.9% (95% CI −6.5 to −15.2) drop in forced expiratory volume in 1 second.

“We believe that the changes in ozone-induced vascular inflammation, fibrinolysis markers, and [heart rate variability] detailed in this study provide the most compelling data to date of the potential for ozone to modulate the cardiovascular system,” wrote Devlin and colleagues.

Potential mechanisms by which ozone might have adverse cardiovascular effects include oxidation of cholesterol in plaque, release of inflammatory mediators from the lung into the bloodstream, and changes to the autonomic nervous system.

“These changes could potentially put a susceptible individual at risk for an adverse clinical event and thus provide biological plausibility to the epidemiology studies that have reported associations between ozone exposure and mortality/morbidity,” the researchers warned in conclusion.

Novel Agent Eases PAH Disability (CME/CE)

The investigational agent riociguat (proposed trade name Adempas) improved exercise capacity and other outcomes in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), two phase III trials showed.

Compared with placebo, the drug provided net gains in the 6-minute walk distance of 36 and 46 meters in patients with PAH and CTEPH, respectively (P0.001 for both), according to Hossein-Ardeschir Ghofrani, MD, of the University of Giessen and Marburg Lung Center in Germany, and colleagues.

And in both types of patients, riociguat resulted in significant improvements on various secondary endpoints, including pulmonary vascular resistance and World Health Organization (WHO) functional class, the researchers reported in the July 25 issue of the New England Journal of Medicine. The findings were initially reported last year at the meeting of the American College of Chest Physicians.

For patients with PAH, riociguat — which will be considered by an FDA advisory committee in August — would join three classes of drugs already approved for that purpose: phosphodiesterase type 5 (PDE5) inhibitors, prostanoids, and endothelin-receptor antagonists.

For patients with CTEPH, however, there are no approved pharmacologic therapies and the standard treatment is pulmonary endarterectomy. But not all patients can undergo surgery, and there is a high rate of recurrence among those who do.

“So in those patients, this drug will be clearly helpful, and in fact is the only drug that has been proven to be effective, as was seen in this trial,” commented Srinivas Murali, MD, of Allegheny General Hospital in Pittsburgh.

Riociguat — a soluble guanylate cyclase stimulator — showed some benefits for both PAH and CTEPH in previous clinical studies. Its safety and efficacy were further evaluated in the PATENT-1 trial of patients with PAH and the CHEST-1 trial of patients with CTEPH.

PAH Trial

The 12-week PATENT-1 trial, which was conducted at 124 centers in 30 countries, included 443 patients (mean age 51; 79% female) who had symptomatic PAH. Half of the patients were not receiving any treatments for PAH, 44% were taking an endothelin-receptor antagonist, and 6% were taking a non-intravenous prostanoid. Use of PDE5 inhibitors and IV prostanoids was not allowed.

The patients were randomized to placebo or one of two riociguat arms — individually tailored doses of up to either 1.5 or 2.5 mg three times daily for 12 weeks, with adjustments made through the first 8 weeks based on systolic systemic arterial blood pressure and signs or symptoms of hypotension. The 1.5-mg group was exploratory only and was not included in the efficacy analysis.

The average 6-minute walk distance at the start of the study was 368 meters in the placebo group and 361 meters in the riociguat group. Through 12 weeks, the distance dropped by an average of 6 meters with placebo and increased by an average of 30 meters with riociguat.

The advantage for riociguat was seen both in the patients who were not receiving any other therapies and in those who were on background therapy. A greater benefit was seen for those with the highest WHO functional classes at baseline.

Secondary endpoints improved as well, including pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, WHO functional class, time to clinical worsening, and the score on the Borg dyspnea scale (P≤0.005 for all).

The drug was associated with a lower rate of serious adverse events. The most common such event was syncope (1% with riociguat versus 4% with placebo).


The CHEST-1 trial was conducted at 89 centers in 26 countries and included 261 patients (mean age 59; 66% female) who had inoperable CTEPH (72%) or recurrent pulmonary hypertension after endarterectomy (28%) and who were not taking an endothelin-receptor antagonist, prostacyclin analog, PDE5 inhibitor, or nitric oxide donor within 3 months of the start of the study.

The patients were randomized to either placebo or riociguat given at an adjusted dose up to 2.5 mg three times daily for 16 weeks.

At baseline, the average 6-minute walk distance was 356 meters in the placebo group and 342 meters in the riociguat group. By the end of the study, the average distance decreased by 6 meters in the placebo group and increased by 39 meters in the riociguat group.

Secondary endpoints that improved with riociguat included pulmonary vascular resistance, NT-proBNP levels, and WHO functional class (P≤0.003 for all).

The most common serious adverse events were right ventricular failure (3% in both groups) and syncope (2% in the riociguat group and 3% in the placebo group).

The rate of discontinuation due to adverse events was 3% with riociguat and 2% with placebo.

There was a greater percentage of deaths in the placebo group (3% versus 1%), although one death from acute renal failure in the riociguat group was considered to be related to the study treatment.

Trial Limitations

Murali pointed out that the use of functional capacity as the primary endpoint in both trials was a shortcoming because “one of the things that we have learned in this field is that functional improvement by itself does not constitute modulation of the disease and improvement in outcomes.”

In an accompanying editorial, Stephen Archer, MD, of Queen’s University in Kingston, Ontario, identified some additional limitations, including the failure to look at the effects of treatment on the right ventricle in both trials.

Speaking to the trial in patients with CTEPH, he noted that the observed improvement in the 6-minute walk distance was less than that previously seen with endarterectomy, which has been associated with a 100-meter increase.

“Since most centers do not perform pulmonary endarterectomy, there may be a temptation to take the easy route and prescribe riociguat,” Archer wrote. “Patients who are suitable candidates for surgery should continue to undergo surgery and not be relegated to an inferior treatment.”

As for the trial in patients with PAH, the major limitation was the modest effect size, he said.

“This is particularly important, since 50% of the patients were receiving no other treatment for pulmonary arterial hypertension and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for pulmonary arterial hypertension,” he wrote.

“The glass may be seen to be half empty because of the modest improvement in 6-minute walk distance with riociguat,” Archer wrote. “However, I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for Group 1 pulmonary hypertension and potentially the first effective oral therapy for inoperable Group 4 pulmonary hypertension.”

Both trials were supported by Bayer HealthCare, which is developing riociguat.

Ghofrani reported receiving grant money through his institution from Bayer and consulting fees or honoraria and support for travel to meetings for the trial or other purposes personally from Bayer. He reported additional relationships with Adelphi Communications, Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and Lilly.

The other authors from the PATENT-1 study group reported relationships with Bayer, Actelion, Novartis, Eli Lilly, Pfizer, GlaxoSmithKline, Adelphi Communications, United Therapeutics, Aires, Bayer Schering, Gilead, GeNo, Regeneron, Liquidia, and UpToDate. Three of the authors are employed by Bayer.

The other authors from the CHEST-1 study group reported relationships with Bayer, Actelion, Pfizer, Adelphi Communications, Lilly, Novartis, GlaxoSmithKline, AOP Orphan, and United Therapeutics. Three of the authors are employed by Bayer.

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