Sanjay Kaul Grades Four Big Trials From ESC 2017

Sanjay Kaul, MD


September 08, 2017

Sanjay Kaul, MD

Here is my Consumer Reports–like star rating of four of the late-breaking clinical trials from the 2017 European Society of Cardiology Congress (1 star = low grade; 5 stars = highest grade) The rating is based on three key attributes: the quantity of evidence as assessed by the effect size and statistical persuasiveness (robustness); the quality of evidence (well-designed, adequately powered trial with excellent trial conduct, including low amount of missing data); and highly desirable benefit-risk balance. Cost is a secondary consideration.


Description: Catheter-based renal denervation versus sham control in patients with uncontrolled hypertension in the absence of antihypertensive medications.

Would you be encouraged to conduct a comparative-effectiveness trial of renal denervation versus optimal medical treatment in refractory hypertension (which is where the unmet need is), given the 5- to 8-mm Hg reduction in 24-hour ambulatory systolic blood pressure (SBP) and office SBP, respectively (or 4- to 5-mm Hg reduction in diastolic BP), observed with renal denervation in patients with mild to moderate hypertension? I personally would be very discouraged, given that the modest BP-lowering effects might actually represent an overestimate ("random high" due to early interim analysis), thereby reducing the likelihood of a win in an adequately designed comparative-effectiveness trial.


Description: Anacetrapib (CETP inhibitor) versus placebo in patients with atherosclerotic vascular disease on intensive statin therapy.

That the 1% difference in the primary endpoint achieved statistical significance has more to do with the sample size (about 30,000) than with the "miracle of medicine." There was no impact on mortality. The treatment effect is not robust enough to overcome the skepticism engendered by one negative trial with torcetrapib and two null trials with dalcetrapib and evacetrapib. Potential safety concerns include adverse trends in BP and renal function, and given the long half-life of the drug, it is not clear whether these signals could become clinically relevant. Finally, one cannot claim that this study provides validation of the HDL hypothesis, given the 17% reduction in LDL-C which would predict the modest 9% relative risk reduction in outcomes observed in the trial.

CANTOS (★★★)

Description: Canakinumab (interleukin-1 beta-blocker) versus placebo in patients with prior myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hs-CRP) on optimal medical therapy.

The modest treatment effect (primarily driven by nonfatal MI) which barely met the threshold P value, together with increased risk for fatal infection and prohibitive cost, make me unenthusiastic about the role of canakinumab in clinical practice. The treatment effect is not robust enough to garner a cardiovascular indication from the US Food and Drug Administration (FDA) based on a single trial. The 150-mg dose barely met the P value threshold, which means that a few extra events in the treatment arm would probably overturn statistical significance! The increased risk for fatal infection complicates the benefit-risk profile. The drug was rejected by the FDA for treatment of gout, a proinflammatory disease, because of safety concerns.

Even the proclamation that CANTOS provides the elusive validation of the inflammatory hypothesis of atherosclerosis is open to debate. I would argue that without a low–hs-CRP arm, one cannot make such a claim. If treatment benefits are evident in the low–hs-CRP arm as well as the high–hs-CRP arm (as was observed with rosuvastatin in the HOPE-3 trial, and not possible to evaluate in JUPITER because patients with hs-CRP < 2 mg/L were not enrolled), can one really claim that the inflammatory hypothesis of atherosclerosis is validated?

The most precise interpretation of CANTOS is that inhibition of IL-1 beta by canakinumab might reduce risk for CVD but at the cost of fatal infection. "Might" is a qualifier acknowledging modest effect size that was barely statistically significant and not sufficient for approval based on one single trial. Also, we don't know whether the treatment effect applies to all inhibitors of IL-1 beta.

Bottom line: Does CANTOS move the needle for the inflammatory hypothesis? Yes, but not beyond any reasonable doubt. I would argue that after three decades of experimentation, one would require a higher burden of proof than "more likely than not."

I don't foresee any clinical utility for canakinumab, given the modest effect, prohibitive cost, and fatal infection risk. Other drugs with a proven track record of safety and affordability, such as methotrexate and colchicine, are going to have a bigger impact on the field provided that the trials (CIRT and LoDoCo) are positive.

The effect on incident lung cancer and lung cancer mortality is intriguing but hypothesis-generating. This might be the only pathway through which the sponsor might be able to get payment coverage by the insurance companies, unless they decide to lower the cost drastically (which is unlikely).

COMPASS (★★★★)

Description: Rivaroxaban 2.5 mg twice daily + 100 mg aspirin versus aspirin alone in patients with stable cardiovascular disease. (The rivaroxaban 5 mg twice daily monotherapy arm did not show a benefit over aspirin alone.)

A 1.3% absolute risk decrease in MACE and a 1.2% absolute risk increase in major bleeding without an increase in intracranial hemorrhage or fatal bleeding is clearly a desirable benefit-risk balance. It's interesting to see risk reduction in cardiovascular death and nonfatal stroke but not in nonfatal MI. Had the trial not been stopped early, perhaps an MI benefit would have become evident. Statistical rules of engagement don't allow an inference of total mortality benefit. Thus, estimates of cost-effectiveness based on mortality advantage are probably not appropriate.

So, while benefit-risk is clearly desirable, thereby earning COMPASS a higher rating, cost is an important consideration that dampens my overall enthusiasm.

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