April 27th, 2015

More Preliminary Signs That PCSK9 Inhibitors May Improve Outcomes

A new analysis of available data from early trials with PCSK9 inhibitors adds to the growing evidence showing that this much-anticipated new class of drugs dramatically lowers LDL cholesterol and offers additional preliminary evidence showing that they are safe and may confer a mortality benefit. But, the authors and other outside experts warn, the outcome findings should be interpreted with caution until long-term, dedicated outcome studies are completed.

In a paper published in Annals of Internal Medicine, a group of researchers combined data from 24 phase 2 and 3 trials that included more than 10,000 patients randomized to treatment with or without a PCSK9 inhibitor. The headline for the study will undoubtedly be the statistically significant 55% reduction in mortality. But it is less clear if the same reports will focus on the fact that there were only 40 deaths in all the trials and the absolute rate of death was extremely low: the death rate was 0.31% (19 of 6187 patients) in the PCSK9 inhibitor group and 0.53% (21 of 3971 patients) in the control group (OR, 0.45; CI 0.23 – 0.86, p= 0.015). There was a similar, but not statistically significant, reduction in cardiovascular mortality and a statistically significant reduction in myocardial infarction.

To no one’s surprise, people treated with PCSK9 inhibitors had a large 47% reduction in LDL cholesterol. In the trials in which PCSK9 inhibitors were tested as an addition to ezetimibe, the PCKSK9 inhibitors resulted in an average 36% reduction in LDL.

In an accompanying editorial, Miguel Cainzos-Achirica and colleagues at Johns Hopkins note that the findings are consistent with previous efforts to assess outcomes with the PCSK9 inhibitors. But they warned that the “included trials were of small or moderate size and mostly had short follow-up periods.” They also pointed out that “little is known about the long-term adverse effects of sustained PCSK9 inhibition, including neurocognitive outcomes and diabetes.”

The cost of PCSK9 inhibitors will also be an important factor in their clinical role, say the editorialists. Although the future cost of PCSK9 inhibitors when they become available is unknown, statins are now mostly available in inexpensive generic formulations and ezetimibe will become generic in the near future.

“Ultimately,” the editorialists conclude, “trials with long follow-up periods together with real-world experience will be necessary to better characterize the safety profile of PCSK9 inhibition, as well as the patient’s tolerance of chronic subcutaneous injections.”

Asked to comment on the study, Sanjay Kaul said that the “bottom line” is that “without data derived from dedicated, long-term outcome studies with prespecified hypotheses, the results of such analyses should be interpreted with a grain of salt!”


4 Responses to “More Preliminary Signs That PCSK9 Inhibitors May Improve Outcomes”

  1. Louis Krut, MB.ChB. MD says:

    Anyone who would attach meaning to a difference in death rate between 0.31% and 0.53%, whatever the p value, has no insight and must be driven by considerations that have nothing to do with scientific validity.

  2. Francis Kempf, MD says:

    Given prior studies looking at other classes of drugs, I think that it will be imperative that long term studies are needed. These drugs will be quite expensive when compared to the current generic statins. They will require parenteral administration. Finally, the insurance companies are going to have stringent pre-authorization protocols for the use of these agents.

  3. Although I am an investigator on anti-PCSK9 antibody trials and have seen some spectacular lipid results, the ultimate net impact on cardiovascular events can only be defined with ongoing prospective event based clinical trials and not from retrospective look and posthoc analysis especially in very low risk populations and relatively short follow up

  4. Let’s avoid the temptation to assume that this expensive drug is going to be a blockbuster. I see very few subjects who will need it. I agree completely with Dr Shah regarding the need for patience and data before excessively promoting this drug.