Authors’ Reply

We are delighted to learn that Drs. Akerström and Rodríguez-Padial are convinced that “the J-curve exists, because there must be a point at which [blood] pressure becomes too low to provide sufficient perfusion to vital organs.” Some investigators have denied the existence of a J-curve, although their own data clearly documented such a phenomenon. For instance, Psaty et al stated that “the association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relation.” However, scrutiny of their data in the 4,902 subjects of the Cardiovascular Health Study (CHS) reveals a J-curve between diastolic blood pressure and the hazard ratio for the risk for myocardial infarction in that this risk was higher in the lowest than in the second lowest blood pressure quintile.

A thorough analysis of many prospective randomized clinical trials consistently reveals a J-shaped relation between blood pressure (more so for diastolic than for systolic) and cardiac events. However, the question is, as Drs. Akerström and Rodríguez-Padial point out, whether the nadir of this J-curve lies within the blood pressure range of treated patients with hypertension. As can be seen from Table 1 , this nadir varies a great deal from study to study but in general is well within a physiologic range of blood pressure.

Table 1

Trials that showed J-curve blood pressure control nadir with lowest cardiovascular disease mortality risk

N 22,576 4,583 10,001 25,620 15,245 4,162 14,703 18,790
Medications Verapamil vs atenolol Nitrendipine vs placebo Atorvastatin 10 mg vs 80 mg Telmisartan vs telmisartan/ramipril Valsartan vs amlodipine Pravastatin vs atorvastatin Valsartan vs captopril vs valsartan/captopril Felodipine
Baseline SBP (mm Hg) 150.8 173.8 131 141.8 153.5 NR 122.7 170
Baseline DBP (mm Hg) 87.1 85.5 78 82.1 86.9 NR 72.3 105
Nadir SBP (mm Hg) 119.2 NR 146.3 130 128 136 135 138.8
Nadir DBP (mm Hg) 84.1 75 81.4 75 79 85 NR 83

ACS = acute coronary syndromes; CAD = coronary artery disease; DBP = diastolic blood pressure; HPL = hyperlipidemia; HTN = hypertension; NR = not reported; ONTARGET = Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; SBP = systolic blood pressure; SYST-EUR = Systolic Hypertension in Europe; TNT = Treating to New Targets; VALIANT = Valsartan in Acute Myocardial Infarction Trial; VALUE = Valsartan Antihypertensive Long-Term Use Evaluation.

With regard to the International Verapamil-Trandolapril Study (INVEST), we will like to emphasize several points. First, similar to all other studies, the analysis was done post-hoc. We agree that this reduces the strength of evidence to some extent. However, we will like to point out that even in the Hypertension Optimal Treatment (HOT) study, which was prospectively designed to do away with the J-curve phantasm, a clear J-shaped relation was found between diastolic pressure and cardiac events in patients who had coronary artery disease.

Second, patients with severe heart failure (HF) were excluded from INVEST. As the inclusion criteria mandated the presence of hypertension as defined by the sixth report of the Joint National Committee, and average prerandomization blood pressure was 149.5/86.3 mm Hg, a pump function sufficient to generate such a pressure was required. Thus, the number of patients with significant left ventricular systolic dysfunction in INVEST would have been very small.

Third, even in the minority of mild to moderate heart failure patients in INVEST, there is ample evidence that systolic blood pressure has a J-shaped relation with outcomes in patients with HF as well. Also, in patients with HF, 2 previous studies showed that higher diastolic blood pressure is associated with a reduction in mortality. Thus, the presence of HF does not change the underlying J-shaped relation of blood pressure parameters with outcomes. We agree with Akerström and Rodríguez-Padial that patients taking HF specific drugs such as angiotensin-converting enzyme inhibitors and β blockers show improved survival. However, ventricular remodeling and improved pump function may actually lead to an increase in blood pressure. This phenomenon has been identified as “paradoxical” hypertension, or reversal of “decapitated” hypertension. We recently analyzed the effect of cardiac resynchronization therapy on systemic hemodynamics in 18 studies in 2,129 patients with heart failure and found a consistent increase in blood pressure after implantation.

Fourth, the low blood pressure of 112/70 mm Hg observed in the Survival and Ventricular Enlargement (SAVE) trial does not apply to INVEST, because INVEST’s inclusion criteria would have excluded patients with such low blood pressure. The recent results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and also the INVEST substudy in patients with diabetes clearly suggest no additional cardiac benefits of lowering systolic blood pressure beyond 140 mm Hg. The observation of a J-curve does not necessarily imply that the low blood pressure per se increases the risk for coronary events. The so-called reverse causation, that is, that blood pressure is low because of poor health (which obviously would increase events), should be considered as well.

In conclusion, the phenomenon of the J-curve is alive and well. It should not prevent us from aggressively lowering blood pressure in most patients with hypertension, but it clearly mandates a more prudent approach in patients with coronary artery disease.

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Dec 22, 2016 | Posted by in CARDIOLOGY | Comments Off on Authors’ Reply

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