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Consciousness of Blood Pressure Is Rising as Details About Possible Remedies Continue to Evolve: Blood Pressure Linked to Sudden Cardiac Death in Heart Failure Patients


Blood Pressure Linked to Sudden Cardiac Death in Heart Failure Patients

In patients with ischemic left ventricular (LV) dysfunction, systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels are inversely related to the sudden cardiac death (SCD), according to the latest report from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) trial investigators. They found that patients whose blood pressure levels stayed > 130/80 mm Hg had a reduced risk for SCD compared with patients with lower blood pressure levels. These results underline the importance of monitoring blood pressure in patients with ischemic LV dysfunction, and it may be useful for identifying lower-risk patients in whom the benefit of primary defibrillator implantation is more limited, writes lead author Ilan Goldenberg, MD (University of Rochester School of Medicine and Dentistry, Rochester, New York) in the Journal of the American College of Cardiology.[6]

Previous data from MADIT-II showed that only about one third of patients who receive an implantable cardioverter defibrillator (ICD) for primary prevention of SCD needed device therapy for ventricular tachyarrhythmias during long-term follow-up.[7] The investigators hypothesized that ICD "firings" would be limited in a lower-risk subset. Low blood pressure was previously shown to be associated with increased all-cause mortality in patients with LV dysfunction and heart failure, but relation between blood pressure levels and risk for arrhythmic mortality in patients with LV dysfunction and heart failure had not been studied.

The MADIT-II trial, which was funded by Guidant (now part of Boston Scientific, Natick, Massachusetts), studied 1232 patients with previous myocardial infarction, ejection fraction ≤ 30%, and New York Heart Association (NYHA) class I-III heart failure who were randomly assigned to receive a prophylactic ICD or conventional medical therapy in a 3:2 ratio and followed up over 20 months.[8] In the latest subanalysis, which was not funded, the independent contribution of SBP and DBP to outcome was analyzed in 1231 patients with baseline blood pressure values, 742 of whom were assigned to ICD treatment and 489 of whom were assigned to conventional therapy.

Multivariate analysis showed that in the patients who received conventional therapy, each 10-mm Hg increase in SBP was independently associated with a 14% decline in cardiac mortality (P = .01) and a 16% decline in SCD (P = .04). Similar trends of 18% and 20%, respectively, were seen with each 10-mm Hg increase in DBP.

In the total study population, defibrillator therapy was associated with an overall significant 32% reduction in the risk for death vs conventional therapy (P = .005). However, among patients with SBP > 130 mm Hg and DBP ≥ 80 mm Hg, there was no survival benefit for ICD therapy (hazard ratios of 1.04 and 1.05, respectively). In contrast, among patients with ICDs and SBP ≤ 130 mm Hg and DBP < 80 mm Hg, there were highly significant risk reductions with the ICDs of 39% and 38% (both P = .002).

Quartile analysis showed that the ICD benefit was consistently positive in the 3 lower SBP and DBP quartiles, but there was no benefit for the ICD in the upper SBP quartile (131-140 mm Hg) or upper DBP quartile (80-85 mm Hg). Two-year mortality among the patients with SBP < 130 mm Hg and DBP ≤ 80 mm Hg was only 17% in the ICD group compared with 25% in the conventional therapy group, whereas the corresponding rates were 13% and 12% in patients with SBP > 130 mm Hg and 11% and 12% in patients with DBP ≥ 80 mm Hg.

The 172 patients who had both SBP and DBP in the upper quartile ranges showed no ICD benefit, whereas in all the other study patients, who had SBP or DBP below the respective upper quartile values, ICD therapy was associated with a significant survival benefit (hazard ratio 0.62; P = .001). There was a significant interaction between ICD and blood pressure for the 2 subgroups, suggesting a significant reduction in ICD efficacy in the patients who maintained raised SBP and DBP levels.

Dr. Goldenberg and coinvestigators note that since the relationship between ICD efficacy and blood pressure persisted after multivariate adjustment for ejection fraction, NYHA functional class, heart rate, and concurrent antihypertensive therapy, the effect of blood pressure appears to have been independent of other health markers in this population. They suggest that the ability to maintain elevated SBP and DBP despite a low ejection fraction may indicate better myocardial reserve, which may be associated with improved survival and reduced risk for cardiac death and SCD. Patients with LV dysfunction and lower blood pressure levels may have "maladaptive activation of catecholamine and other neurohormonal counterregulatory systems that potentially contribute to increased risk for arrhythmias and death."


In an accompanying editorial,[9] Javed Butler, MD, MPH, and Angel Leon, MD (Emory University, Atlanta, Georgia) comment that these results "obviously must be taken with caution." They point out that "this was a secondary analysis with limited power on data not collected specifically to answer this question and the patient population was restricted to the enrollment criteria of the MADIT-II study." The results need to be validated in a wider population, they say, while welcoming the study in the search to identify patients who are likely to benefit most (or least) from a defibrillator.

Japanese Study Adds to Controversy About ARBs and Cardiovascular Benefits Beyond Blood-Pressure Lowering

According to Japanese investigators who conducted a clinical trial of aggressive (by Japanese standards) blood-pressure lowering, addition of the angiotensin receptor blocker (ARB) valsartan to conventional antihypertensive treatment prevents more cardiovascular events than increasing the dose or number of standard drugs. The Jikei Heart Study, which was funded by the Jikei University School of Medicine (Tokyo, Japan) and Novartis Pharma KK (Japan), was set up to investigate the effect of blood pressure control to a target of < 130/90 mm Hg with conventional treatment, with or without valsartan, in a large Japanese population representative of the cardiovascular continuum of disease. Few large-scale clinical trials with ARBs -- or any other cardiovascular trials -- have been carried out in Japan, the investigators note in their report, published in The Lancet.[10] The first results of their study were presented at the 2006 World Congress of Cardiology in Barcelona.

Between January 2002 and December 2004, the Jikei Heart Study enrolled 3081 Japanese patients (mean age 65 years, one third women) with a mean "borderline" baseline blood pressure of 139/81 mm Hg. All of the patients were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were randomly assigned either to valsartan (40-160 mg per day) or to treatment without ARBs (controls).[11] The primary endpoint was a composite of cardiovascular morbidity and mortality. Components of the endpoint included hospital admissions for stroke or transient ischemic attacks (TIA), congestive heart failure, or angina pectoris; myocardial infarction; dissecting aortic aneurysm; doubling of serum creatinine; or transition to dialysis. Analysis was by intention to treat. The study was stopped early, in January 2006, due to a greater-than-expected risk reduction in the valsartan group.

During a median follow-up, the primary endpoint was recorded in 92 (6.0%) patients given valsartan compared with 149 (9.7%) controls. The absolute risk was 21.3 vs 34.5 per 1000 patient years, for a hazard ratio of 0.61 (95% confidence interval, 0.47-0.79; P = .0002), after adjustment for sex, age, hypercholesterolemia, diabetes, smoking, and concomitant antihypertensive treatment.

The investigators say that this difference was mainly due to a 40% risk reduction in stroke and TIA, a 65% risk reduction for angina pectoris, and a 47% risk reduction in heart failure in the valsartan group compared with the control group. There was no difference in mortality, myocardial infarction, or progression of renal disease between the 2 groups. (Because the study ended prematurely, it was not powered to detect changes in cardiovascular or all-cause mortality.) Only 2.5% of patients reported any adverse event, with no significant differences between the 2 treatment groups.

Lead author Seibu Mochizuki, MD, PhD (The Jikei University School of Medicine) and fellow investigators believe that because blood pressure control was comparable between the treatment groups, it cannot fully explain the additional cardiovascular benefits seen in the valsartan arm. During the study, blood pressure fell by essentially equal amounts, to 131/77 mm Hg in the valsartan group and to 132/78 mm Hg in the control group. As further evidence of the parity of blood pressure lower, 75% of patients in the valsartan group and 70% of patients in the control group had achieved the target blood pressure of < 130/80 mm Hg at the end of the trial. Only 4% of patients in each group still had blood pressure > 140/90 mm Hg.

When the results of the study were first presented in Barcelona, Prof. Mochizuki said, "We achieved the lowest blood pressure value ever set in a morbidity/mortality outcomes trial and saw tremendous benefit for the valsartan arm in reducing the risk of cardiovascular events as well as stroke."


In an accompanying commentary in The Lancet,[12] Jan A. Staessen, MD, PhD, and Tom Richart, MD, MBE (University of Leuven, Belgium) say that the Jikei Heart Study demonstrates the safety of and efficacy of aggressive antihypertensive treatment in preventing cardiovascular complications, if "aggressive means optimization of treatment at acceptable tolerance and the combination of several classes of antihypertensive drugs, each to be prescribed at the lowest dose to attain targets." However, it does not show that valsartan, or any other ARB, might confer benefits beyond blood pressure lowering, they assert.

While they acknowledge the difficulties involved in conducting randomized clinical trials in Japan, several weaknesses in the conduct of the study mean that the investigators' main conclusions "cannot be accepted at face value." They say that the major weakness of the study was the compromises the investigators had to accept to make their trial feasible. These include a smaller sample size and a lower incidence of hard events than in many other trials and a PROBE (prospective, randomized, open-label, blinded endpoints) design that did not protect against possible investigator bias in reporting events or admitting patients to hospital. Admission was especially important, they say, because it formed part of the primary outcome measure. In addition, the standardized daily doses of non-ARB therapy did not catch up with the addition of valsartan until the second year of follow-up.

Finally, Drs. Staessen and Richart cite comprehensive reviews of the literature -- including those by the Blood Pressure Lowering Treatment Trialists' Collaboration[13] and researchers at University College London[14] -- that reached the conclusion that ARBs did not have additional protective benefits compared with conventional treatment beyond those attributable to control of blood pressure.

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