CVD Risk from High Systolic BP, LDL-C Cumulative, Independent

Susan Jeffrey

August 29, 2016

ROME, ITALY — A new study suggests that the cardiovascular risk associated with higher levels of systolic blood pressure (SPB) and LDL cholesterol are independent and cumulative, and even modest lowering of these risk factors may offer dramatic benefits in preventing cardiovascular disease[1].

Using a Mendelian randomization study design, researchers found that long-term exposure to the combination of 1 mmol/L (18 mg/dL) lower LDL-C and 10 mm Hg lower SBP was associated with an almost 90% lower risk of major vascular events.

"We conclude from this that LDL cholesterol and systolic blood pressure have independent, multiplicative, and cumulative effects on risk of cardiovascular disease," said Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI).

Dr Brian Ference

Because these effects are multiplicative and cumulative, he said, long-term exposure to the combination of "modestly" lower LDL-C and SBP "has the potential to dramatically reduce the lifetime risk of cardiovascular events, even among persons with apparently normal cholesterol and blood-pressure levels.

"Our study confirms that cardiovascular events are largely preventable, and it suggests that the prevention of cardiovascular disease can be substantially improved and substantially simplified simply by designing prevention programs that focus on promoting long-term exposure to lower LDL and lower blood pressure," he added.

"I think, however, that public-prevention programs, however they're adapted to the local risk-factor burden or the local custom or the local health care systems, can now all be recalibrated slightly toward a common goal of keeping LDL and systolic blood pressure low as long as possible to achieve the maximum possible benefit," Ference told heartwire from Medscape.

The results were presented here at the European Society of Cardiology (ESC) 2016 Congress.

Ideal Risk-Factor Profiles Rare

Observational research has shown that people able to maintain ideal risk-factor profiles over the whole of adulthood have a very low lifetime risk of cardiovascular disease, he said. However, fewer than 5% are able to maintain such levels, he noted.

"By contrast, Mendelian randomization studies have consistently demonstrated that both LDL cholesterol and systolic blood pressure have causal and cumulative effects on risk of cardiovascular disease," he noted.

The causal effect of long-term exposure to the combination of lower LDL and lower systolic blood pressure, however, is unknown, he noted. Results of the recent Heart Outcomes Prevention Evaluation 3 (HOPE-3) trial showed that combination therapy with lipid-lowering agents and antihypertensive agents did not reduce events over use of lipid-lowering agents alone.

"The results of this trial have caused some to question the synergy between LDL cholesterol and systolic blood pressure on the risk of cardiovascular events, particularly among persons without hypertension," Ference said.

In the current study, the researchers aimed to evaluate this causal effect of long-term exposure to lower LDL and lower SBP on the risk of cardiovascular disease, and secondarily, he said, "to evaluate the potential clinical benefit of a simplified prevention strategy that focuses on 1 mmol/L lower LDL and 10 mm Hg lower systolic blood pressure for a long period of time."

To approach the question, they used a 2x2 factorial Mendelian randomization study. They used genetic and cardiovascular risk-factor data from 102,773 individuals who had participated in one of 14 prospective cohort or case-control studies to calculate genetic scores for each patient based on genetic polymorphisms known to be associated with LDL or SBP and the number of alleles associated with raised LDL or SBP levels.

"It's important to note here that our study actually had very little to do with genetics," Ference said. Genetic scores were not used to predict risk, he said, but as "convenient instruments that allowed us to naturally randomize people to various groups."

On that basis, they divided patients into four groups: a reference group; a group with an LDL genetic score below the median, resulting in lower LDL levels; a group with an SBP score below the median, resulting in naturally lower blood pressure; and a group with both LDL and SBP below the median, resulting in both lower LDL and lower SBP.

The primary outcome was a composite of the first occurrence of major vascular events, including coronary death, nonfatal MI, nonfatal stroke, or coronary revascularization.

Over as many as 32 years of follow-up, a total of 14,368 events occurred. They found that the combined effect of lower LDL and lower SBP "had independent, multiplicative and cumulative effects on the risk of cardiovascular disease," he said.

Combined exposure to lower LDL and lower SBP was significantly greater than the effect of LDL alone (P=1.4x10-14) and significantly greater than the effect of lowering blood pressure alone (P=1.8x10-23).

"In fact, because the effect of lower blood pressure and lower cholesterol was both multiplicative and cumulative over time, the effect of combined exposure to 1 mmol/L lower LDL and 10 mm Hg lower systolic blood pressure was associated with an 86.1% lower risk of cardiovascular disease," he said (odds ratio 0.139, 95% CI 0.114–0.170, P=1.6x10-83).

The effect of combined exposure to lower LDL and lower SBP was a consistent 80% to 90% reduction across all of the end points considered, including an 84% reduction in coronary heart disease mortality that translated into a "smaller but still significant" reduction in all-cause mortality, he noted.

The effect was similar in men and women, smokers and nonsmokers, people with and without diabetes, and "importantly," in people with LDL-C above and below 3.5 mmol/L and those with SBP above and below 120 mm Hg, "suggesting the benefit of combined exposure to lower LDL and lower systolic blood pressure would extend to persons who have apparently normal blood-pressure and cholesterol levels."

Missing the Boat

Moderator for the press conference, Dr Joep Perk (Linnaeus University, Kalmar, Sweden) was very impressed with the results.

"I started out as a clinician, but then I discovered the enormous potential in prevention and working with patients' lifestyle, and that has always been my interest," Perk told heartwire . "As a clinician I've seen the strengths in this, but to see this in figures is very encouraging.

"It also says one important thing—that if you as a doctor don't deal with lifestyle, don't help the patient in that direction, you simply miss the boat. You can give patients as many drugs as you want, but you can't replace lifestyle," he said.

At their institution, after successful treatment of cardiac events, they emphasize to patients that "this has been a severe warning; that's the 'yellow card,' and you can't afford one more," he added, referring to penalty warnings given in soccer. They are using a new approach to prevention that has all patients leaving the cath lab with a "personal trainer," usually a nurse, to coach them on lifestyle change, he said.

The study had no external funding. Ference reports receiving research grants from Merck, Amgen, and Esperion Therapeutics, and consulting fees from Merck, Amgen, and Ionis Pharmaceuticals.

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