ASCOT Analysis Fuels Debate Over JUPITER-Based CRP Indication for Statins

November 19, 2010

November 18, 2010 (Chicago, Illinois) — The addition of high-sensitivity C-reactive protein (hs-CRP) measurements didn't much improve conventional risk assessments in patients with hypertension and other CV risk factors but normal or only modestly elevated LDL-cholesterol levels in a post hoc analysis of an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) lipid-lowering arm [1].

Moreover, among patients in the analysis who had been randomized to receive atorvastatin (Lipitor, Pfizer), a significant reduction in LDL-C corresponded to a significant drop in CV-event risk at six months. But a significant fall in hs-CRP levels did not predict a decrease in CV events.

Dr Peter S Sever

In the current analysis, "neither baseline nor on-treatment CRP [measures] provide useful information about the efficacy of statin treatment to reduce cardiovascular events beyond LDL-cholesterol reduction," concluded ASCOT co-chair Dr Peter S Sever (Imperial College, London, UK) here at the American Heart Association 2010 Scientific Sessions.

"These results do not support current proposals to measure CRP in the clinical setting, either to assign statins to individuals on the basis of an elevated CRP alone or to monitor CRP levels as an indicator of the efficacy of statin treatment," he said.

The ASCOT analysis, according to Sever, challenges the recent broadening of rosuvastatin (Crestor, AstraZeneca) indications by the US FDA based on the JUPITER trial, which compared the drug with placebo in >17 000 adults with normal LDL-C and hs-CRP >2.0 mg/L [2].

As covered by heartwire , statin recipients in JUPITER showed a 44% drop in risk of nonfatal MI or stroke, hospitalization for unstable angina, coronary revascularization, or CV death (hazard ratio 0.56, 95% CI 0.46–0.69) over about two years.

Based on the trial, rosuvastatin labeling was modified to include reduction of cardiovascular-event risk in persons with normal LDL-C who don't have clinical evidence of CAD but are at increased risk based on age, CRP levels, and--tightening up a bit on criteria used in JUPITER--at least one other cardiovascular risk factor.

Speaking with heartwire , Sever pointed out that in the ASCOT analysis, adding CRP to a conventional risk assessment based on elements of the Framingham risk score improved risk prediction, but not by much.

"If you measure their total-to-HDL ratio, if you measure their blood pressure, if you've decided whether or not they smoke, [and consider] their age and their sex, that tells you all you need to know about their risk," he said. "Putting CRP in there doesn't alter the [risk-status] classification of people, and that suggests to me that it doesn't have added value."

That means CRP doesn't have a practical role in deciding whether to initiate statin therapy, according to Sever.

"In patients with hypertension, they're on statins. In patients with diabetes, they're on statins. In patients with stable coronary artery disease, they're on statins. There's no additional benefit to be gained from measuring CRP."

Dr Donald Lloyd Jones

As the assigned discussant for Sever's presentation, Dr Donald Lloyd Jones (Northwestern University, Chicago, IL) said the take-home message of the analysis is that it adds to "a very large body of literature suggesting minimal clinical utility for CRP levels in risk assessment and decision making for lipid-lowering therapy and adds to a small and somewhat mixed literature examining the utility of on-treatment CRP levels."

The analysis, he said, questions "whether CRP is something we need to be spending our time on."

Discussing the ASCOT analysis with heartwire , Dr Elliot Antman (Brigham and Women's Hospital) seemed to agree that CRP probably has a limited risk-stratification role.

Dr Elliot Antman

"For patients with a very low risk-factor profile [based on standard risk assessment], a measurement of CRP might be considered as sort of a general screen," he said. But, "I'm not so convinced that it's going to provide a lot of incremental value for deciding who should start on a statin."

If all one has to go on is CRP level, there's evidence that it can be predictive, Antman observed. "But if you start giving me incremental information like this person smokes, or has diabetes, or has hypertension, then the amount of benefit I'm gaining from knowing the person's CRP is dropping with each new piece of information you give me."

Others heartwire spoke to had misgivings about the ASCOT analysis. "I'm not as convinced as Dr Sever that this damages the CRP hypothesis," said Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD). "We have good data that statin therapy is pretty safe and effective in 90% to 95% of people. It would be a real disservice if the message got across to people that CRP [measurements are] worthless and shouldn't be part of the screening process for statin therapy."

Dr Paul Ridker

JUPITER principal investigator Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) observed for heartwire that the trial "evaluated the utility of statins in a group of patients who otherwise would never be treated." They didn't qualify for statin therapy, he said; "they had an LDL below current standards, and they had Framingham scores averaging 10 or below. What they had in common was an elevated CRP, and clearly they benefited," he said.

"The whole issue with any biomarker is quite simple. The question you have to ask is, does the biomarker identify a population that wouldn't otherwise be treated, and is there evidence that such a population benefits from therapy? JUPITER overwhelmingly says yes."

Dr Christopher Cannon

As a panelist discussing the ASCOT analysis after Sever's presentation, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) said he sees it and JUPITER as "complementary." The observational, retrospective ASCOT analysis suggests that CRP measurement doesn't add much to risk assessment in patients already with statin indications. "But it was shown very nicely in a prospective trial [JUPITER] that if you do identify someone, an older patient with normalish LDL, then they'll show benefit [from statin therapy]."

To heartwire , Lloyd Jones said, "I think to characterize the JUPITER population as a low-risk population is incorrect. While their LDLs were modest, they had plenty of other things that contributed to their risk. The mean patient was solidly in the intermediate-risk range. These are patients who would potentially benefit from LDL reduction. The ASCOT group is an even higher-risk population, so I'd agree with Dr Cannon on that point."

Dr Roger Blumenthal

Blumenthal joined Ridker and Cannon in considering the JUPITER population to be low CV risk by standard assessments. "Clearly, JUPITER was a game changer, and the message that they're putting out, that CRP isn't worth measuring, I think is completely wrong," he said.

Even the new guidelines that just came out about primary-prevention screening say if you meet the JUPITER criteria . . . it's certainly reasonable to initiate statin therapy.

The ASCOT analysis was based on 485 patients from UK and Irish centers who reached a composite end point that included CV death, nonfatal MI, coronary revascularization, or fatal/nonfatal stroke, who were age- and sex-matched to 1367 patients in the control group who hadn't suffered one of those events. They were followed for 5.5 years.

Baseline levels of hs-CRP and LDL-C were significantly correlated with each other at p<0.0001. And both parameters were significantly predictive of a composite CV end point that included CV death, nonfatal MI, coronary revascularization, or fatal/nonfatal stroke, at an odds ratio (OR) of 1.31 (95% CI 1.10–1.56, p=0.002) for LDL-C and OR 1.19 (95% CI 1.05–1.34, p=0.006) for every one standard-deviation increase in hs-CRP.

Also, according to Sever:

  • Including hs-CRP into modified and full Framingham risk models only minimally improved prediction of cardiovascular events.

  • The addition of on-treatment hs-CRP measurement to on-treatment LDL-C measurement didn't improve the prediction of patient response to statin therapy.

And, among patients assigned to atorvastatin:

  • IBaseline hs-CRP did not predict the magnitude of the drug's effect on cardiovascular end points.

  • Over six months of therapy, the median LDL-C fell by 40.3% and median hs-CRP dropped 27.4%.

Lower on-treatment LDL-C but not hs-CRP was associated with a highly significant reduction in cardiovascular events over six months:

  • An LDL-C less than the median of 2.1 mmol/L, compared with LDL-C at or higher than the median, predicted a reduction in the composite end point at an adjusted OR of 0.41 (95% CI 0.22–0.75, p=0.004).

  • But an hs-CRP less than the median of 1.83 mg/L, compared to hs-CRP at or higher than the median, showed no such predictive effect at an adjusted OR 0.86 (95% CI 0.49–1.51, p=0.60).

"It is clear that achievement of low LDL-cholesterol levels confers great benefit, and there's no added benefit by achieving a lower CRP level," Sever said in his presentation.

Blumenthal observed that "even the new ACC/AHA guidelines that just came out about primary-prevention screening say if you meet the JUPITER criteria, for men at least aged 50 and women at least age 60 with a high CRP on two occasions, it's certainly reasonable to initiate statin therapy."

The guidelines make that a class IIa recommendation at a level of evidence B, also requiring an LDL-C <130 mg/dL and absence of clinical heart disease, diabetes, or severe inflammatory conditions [3]. They also give CRP for assessment of asymptomatic, otherwise–intermediate-risk men <50 years and women <60 years a class IIb recommendation at a level of evidence B.

Ridker emphasized that the ASCOT analysis was post hoc and said it was "quite underpowered for addressing the issues they're asking."

In his formal comments after Sever's presentation, Lloyd Jones acknowledged that the analysis has limitations. "It's a post hoc analysis of a previously published trial," he said, "and we must take it with a grain of salt. It was a particularly high-risk primary-prevention cohort, and it's fair to say there were a relatively small number of events. But I think it's also fair to say it's similar to the number of events that were in JUPITER."

The ASCOT lipid-lowering trial was funded by Pfizer. Sever reports receiving research grants from Pfizer; being on a speakers' bureau for Pfizer, Servier, and Novartis; receiving honoraria from Pfizer and Novartis; and being a consultant or advisory board member for Pfizer and Servier. Lloyd Jones and Blumenthal report no relevant financial disclosures. Cannon reports grants from AstraZeneca, Merck, and Roche and being on the speakers' bureau for Abbott, Bristol-Myers Squibb, and Pfizer. The JUPITER trial was sponsored by AstraZeneca. Ridker has received grant support and consulting fees from AstraZeneca and is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and have been licensed to Siemens and AstraZeneca.

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