June 20, 2011 (Milan, Italy) — Dutch researchers have forwarded a tantalizing hypothesis here at the European Society of Hypertension (ESH) European Meeting on Hypertension 2011, which, if it plays out, could have consequences reaching far beyond the world of hypertension. They report that patients who have naturally high levels of the enzyme creatinine kinase (CK)--who are already known to have a higher risk of hypertension than those with lower levels of CK--appear to have attenuated platelet aggregation, which could indicate they are at higher risk of bleeding when taking anticoagulants such as clopidogrel.

Around 50% of black people and 25% of whites have high CK, hypertension-prone phenotypes, Dr Lizzy M Brewster (Academic Medical Center, Amsterdam, the Netherlands) told a late-breaking clinical-trial session here yesterday. "We were curious whether the high serum CK in some subjects would affect platelet aggregation," she explained. "We found, with increasing CK concentrations up to the limits found in the general population, platelet aggregation actually can be completely abolished. We were quite surprised to find this, because we thought, 'If it's this strong an effect, why has no one seen this before?' "

Brewster and her colleagues then went on to perform a systematic literature search, to June 2011, and identified over 5000 papers where bleeding risk was compared between blacks and whites, as a rough indicator to compare high-CK with low-CK phenotypes. "What we found is that black people have quite a high risk for any bleeding. For example, in patients with ST-elevation MI who underwent fibrinolysis, the relative risk was 1.4. We also found that black women have a four times greater mortality risk during childbirth because of bleeding, but most astounding was the finding that when clopidogrel was used in blacks they have a higher relative risk of bleeding, of 3.3; this is quite surprising because it was actually thought this group of people would have a lower risk because they are slow metabolizers of the prodrug of clopidogrel."

Intriguing, "Off-the-Wall" Findings Need to Be Confirmed

Session chair Dr Tony M Heagerty (University of Manchester, UK) called the new findings "intriguing. In hypertensive patients there is a literature suggesting an increased 'thickness' of the blood--increased viscosity, increased erythrocyte sedimentation rate [ESR], increased fibrin levels, decreased plasma volume--and yet here we have the possibility that those particular individuals [high-CK phenotypes] have a greater bleeding tendency when they should have less, so it's difficult to follow."

Brewster pointed out, however, that "in the black population there is greater hypertension risk, but relatively lower risk of myocardial infarction," and she suggested that high CK levels in many of these people could have "clopidogrel-like effects, leading to greater bleeding risk."

This is completely off-the-wall. It's going to open a lot of questions.

Although this would be protective in certain circumstances, it may also mean that patients with high CK should not be taking clopidogrel, she warned, although she acknowledged that more data, including prospective trials, are needed to confirm this. If this turns out to be a real effect, it will have many important clinical implications, she says.

Asked to comment on the findings for heartwire , Dr Peter Sleight (University of Oxford, UK) said: "It was a very interesting presentation, really completely off-the-wall. It's going to open a lot of questions and it's something to be mindful of."

If Findings Are Proven True, Test CK Before Giving Anticoagulation

Brewster did not formally present lots of data; rather, she talked through the findings of the platelet-aggregation studies she and her colleagues performed and touched briefly on the findings of the literature search. The theory would, she said, explain the results shown in the CHARISMA study, where those with established vascular disease who received dual antiplatelet therapy (aspirin plus clopidogrel) saw no benefit and in fact had greater bleeding than those who took aspirin and placebo. There was also a suggestion of harm in a subgroup of CHARISMA patients, the primary-prevention or "asymptomatic group."

"High serum CK might attenuate platelet aggregation and maybe--of course, we're not sure, we don't have enough data yet--but maybe high CK confers a low risk of thrombotic events and a higher bleeding risk. The point I want to make is, when active CK is in serum it apparently 'eats away,' so to speak, the ADP such that ADP-dependent platelet aggregation is reduced."

Maybe high CK infers a low risk of thrombotic events and a higher bleeding risk.

In an interview with heartwire , Brewster said in their studies they used the highest tertile of CK in the general population to denote "high," which translated into anything above 150 IU. She added that it is also "quite complicated," because CK can increase exponentially at other times--for example, if people perform strenuous exercise, they can have CK levels in the region of 3000 to 4000 IU, she noted. "It is a dose-effect relationship, and it's biologically plausible, but we were actually quite surprised to find it," she reiterated.

And although the exercise effect is temporary, patients on clopidogrel should know that if they exert themselves significantly their bleeding risk is higher, she warns. CK levels also rise exponentially, again albeit temporarily, following MI and stroke, she noted. "Those are all situations with high serum CK, and we will study these subgroups and see whether our findings have clinical relevance." She stressed also that this is something specific not to one ethnic group but to those with high CK phenotypes.

Brewster said that if this hypothesis bears out, "the clinical implications would be that CK should be routinely tested in patients who are set to receive anticoagulation. If it's high you need to wonder if you would give clopidogrel because these people have, actually, a natural clopidogrel."

Could CK Be Used as a Biomarker for Difficult-to-Treat Hypertension?

Meanwhile, a related late-breaking poster presentation by one of Brewster's colleagues, Dr Inge Oudman (Academic Medical Center), focused on the hypertensive risk associated with high CK activity. "We have previously reported that high CK is the main predictor of high BP in the general population," Oudman explained.

Dr Inge Oudman

The new analysis was based on 1444 subjects (503 of whom were white European, 292 South Asian, 580 black, and 69 other). Subjects with treated, uncontrolled hypertension were two times more likely to have high CK levels than those with controlled BP (odds ratio 2.2), independent of age, sex, body-mass index, glucose, or ethnicity, she said.

"Focusing on CK in hypertension might provide new clues as to how to improve care to patients with treated, uncontrolled hypertension." CK may have a role as a potential biomarker for difficult-to-treat hypertensives, she concluded.

Brewster said: "We have found in a general population that people with high CK, regardless of ethnicity, typically would be the people who have high BP, so they get treated more often, but the treatment fails more often, so we are trying now to use baseline CK as a measure of difficult-to-treat hypertensive patients.

"If doctors are aware of this beforehand, they can, for instance, start combination therapy, because you would want to reduce the BP faster and to a greater extent in these patients."

Heartwire from Medscape © 2011 

Cite this:  - Medscape - Jun 21, 2011.