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Hypertension is a common risk factor for peripheral arterial disease (PAD). Guidelines suggest treating PAD patients to a blood pressure <130/80 mm Hg; therefore, our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes. We performed a post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy, a randomized clinical trial, which included hypertensive patients with concomitant PAD and coronary artery disease. There were 2699 PAD patients followed for a mean of 2.7 years (60 970 patient-years). The primary outcome, all-cause death, nonfatal myocardial infarction, or nonfatal stroke, occurred in 16.3% of PAD patients versus 9.2% without PAD (adjusted hazard ratio: 1.26 [95% CI: 1.13 to 1.40]; P<0.0001). The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg. PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome, although individuals without PAD did not. PAD patients may require a different target blood pressure than those without PAD.
Screening programs have detected peripheral arterial disease (PAD) in up to one fourth of individuals over the age of 50 years and/or with symptoms of claudication.1 In addition to the high prevalence of PAD, this disease is well documented to be associated with increased cardiovascular mortality.2–5 In fact, PAD may portend a worse prognosis for adverse cardiovascular outcomes than coronary artery disease (CAD).6–8
Furthermore, although most PAD patients have hypertension, there are very limited evidence-based data to guide hypertension management. A large international registry documented hypertension in >80% of PAD patients.9 The use of β-blockers was 43%, angiotensin-converting enzyme inhibitors was 47%, diuretics was 46%, calcium antagonists was 40%, angiotensin receptor blockers was 23%, and other antihypertensive medications was 12%, but the optimal level for blood pressure control in PAD patients is lacking. Recent guidelines, based largely on consensus opinion, advocate treating hypertension among patients with PAD to a goal blood pressure <130/80 mm Hg.10
This was a prespecified post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy (INVEST). The aims of the study were 2-fold, to examine the effect of average treated blood pressure on adverse outcomes in CAD patients with PAD and to compare 2 antihypertensive strategies among this population.
INVEST was an international randomized trial involving 14 countries that compared the effects of a calcium antagonist-based strategy (verapamil SR±trandolapril) with a β-blocker–based strategy (atenolol±hydrochlorothiazide) for hypertension among older patients with CAD. Enrollment began September 1997, and follow-up was completed February 2003. The study was conducted according to principles of the Declaration of Helsinki. Local ethics committees approved the protocol, and written informed consent was obtained from all of the subjects. The protocol and main outcomes have been described in detail.11,12 Patients were eligible if they were ≥50 years old with hypertension and clinically stable CAD. Individuals with New York Heart Association class I to III heart failure were eligible for enrollment. Patients with contraindications to the treatments were excluded. Baseline characteristics and past medical history were recorded by each site physician investigator. On the baseline form, one of the questions asked whether the patient had a physician documented history of peripheral vascular disease (yes or no). Detailed information regarding this diagnosis was not available. To be consistent with current nomenclature, peripheral vascular disease was referred to throughout the form as “PAD.” Health-related quality of life (the patient’s subjective well being) was ascertained from a 4-item questionnaire asked at the beginning of each study visit (excellent, good, poor, or fair).13 Protocol-scheduled follow-up visits occurred every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled. Blood pressure was recorded according to guideline recommendations with the patient seated for ≥5 minutes with his or her feet on the floor.11 Data were obtained from a mean of 2 cuff blood pressure measurements. Average blood pressure over the follow-up period was assessed from the blood pressure recorded at each visit.
From the overall study cohort at baseline, patients were grouped into those with PAD versus those without PAD. Patients with PAD were further analyzed according to their randomized treatment strategy (calcium antagonist versus β-blocker). The primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Additional individual outcomes were all-cause mortality, cardiovascular mortality, total MI as fatal MI plus nonfatal MI, and total stroke as fatal stroke plus nonfatal stroke. There were 2 additional composite outcomes for these analyses, an event in the primary outcome or poor/fair quality of life at the final visit and an event in the primary outcome or first occurrence of a vascular procedure during follow-up. Vascular procedures were defined as carotid endarterectomy/stent, amputation, percutaneous peripheral vascular intervention, or aortic aneurysm resection/repair/stent.
Outcomes were adjudicated by a blinded events committee by reviewing documentation of pertinent patient records, hospital records, and death registries. The cause of death was adjudicated as cardiovascular versus noncardiovascular. Because all of the patients had ischemic heart disease, all of the cardiovascular deaths were further adjudicated as ischemic heart diseases (acute MI, arrhythmic, or nonarrhythmic), cerebrovascular disease, or indeterminate disease. Nonfatal MI was defined as an elevation in troponin I or T greater than the upper limit of normal or an elevation in the creatine-kinase MB isoenzyme with ischemic symptoms and/or ischemic electrocardiographic changes. Nonfatal stroke was defined as a sudden onset of a neurological deficit that persisted for >24 hours as confirmed by appropriate imaging or a neurology consult.
Data were analyzed in the intention-to-treat population. Baseline characteristics were reported as frequencies. Continuous and categorical variables were compared with Student t test and the χ2 test, respectively. Kaplan–Meier survival analysis was used to assess the time to a first event for the primary outcome. Hazard ratios (HR) and 95% CIs for adverse outcomes were constructed with a Cox proportional hazard model adjusted for confounding variables identified with a stepwise selection procedure. This was also used to analyze follow-up blood pressures and subjective well-being responses. The mean follow-up blood pressure was obtained from those recorded on randomized treatment. For those with a primary outcome event, the blood pressure obtained at the visit before the event was used to avoid confounding (eg, hospitalization or medication change). A P<0.05 was considered significant. All of the analyses were performed with SAS software version 9.1 (SAS Institute, Inc).
Among the 22 576 subjects in the INVEST patient cohort, there were 2699 patients (12%) with PAD and CAD at baseline. The baseline characteristics of patients with and without PAD are summarized in Table 1. Patients with PAD were older and had more comorbidities than patients who did not have PAD. In addition, PAD patients had a lower quality of life. Among those with PAD, there were 1345 patients assigned the calcium antagonist strategy and 1354 patients assigned the β-blocker strategy (Table 2). There were no differences in baseline characteristics according to the randomized treatment groups. There were 2.5% of patients lost to follow-up.
Over a total follow-up of 60 970 patient-years (mean: 2.70 years; median: 2.68 years), the incidence of the primary outcome was significantly greater among those with PAD versus those without PAD (16.3% versus 9.2%; adjusted HR: 1.26 [95% CI: 1.13 to 1.40]; P<0.0001; Figure 1). A sensitivity analysis was done by excluding those with baseline MI and stroke, and the excess risk associated with PAD was essentially unchanged (adjusted HR: 1.27 [95% CI: 1.08 to 1.48]; P<0.0001). Quality of life poor/fair during the last visit was reported in 29.9% in the PAD group versus 21.7% in the group without PAD (P<0.0001). Individual cardiovascular outcomes are displayed in Figure 2. Predictors of an increased likelihood for the primary outcome are displayed in Table 3.
More patients with PAD achieved a mean blood pressure <130/80 mm Hg compared with those without PAD (31.4% versus 28.4%; P=0.001; Table 4). There was evidence for a J-shaped relationship between the primary outcome and average treated diastolic blood pressure for both PAD and non-PAD patients, and the best outcomes (lowest HRs for the primary outcome) were observed with an average diastolic blood pressure of 60 to 90 mm Hg. The J-shaped relationship was especially evident among PAD patients and average systolic blood pressure, even after controlling for the level of blood pressure that was achieved (Figure 3). The HRs of the primary outcome for average systolic blood pressure (PAD versus no PAD) were 1.69 versus 0.99 for ≤110 mm Hg (P=0.04), 1.02 versus 0.96 for 135 mm Hg (P=0.91), 1.01 versus 1.05 for 145 mm Hg (P=0.65), and 1.65 versus 1.68 for 170 mm Hg (P=0.23). Therefore, among PAD patients, the best outcomes were observed with an average treated systolic blood pressure of 135 to 145 mm Hg.
Among PAD patients, the incidence of the primary outcome was not significantly different between the treatment strategies, although trends favored the calcium antagonist strategy, at 15.5% with a calcium antagonist-based strategy versus 17.1% with a β-blocker–based strategy (HR: 0.89 [95% CI: 0.74 to 1.07]; P=0.21; Figure 4). Likewise, an event in the primary outcome or first occurrence of a vascular procedure was not different, at 17.5% versus 18.2% (HR: 0.94 [95% CI: 0.77 to 1.13]; P=0.50). However, an event in the primary outcome or poor/fair quality of life was 36.5% among those assigned the calcium antagonist strategy versus 41.0% among those assigned the β-blocker strategy (HR: 0.87 [95% CI: 0.77 to 0.99]; P=0.031).
Our analysis found that hypertensive CAD patients in INVEST with concomitant PAD had a 26% increased risk of death, MI, or stroke compared with patients without PAD at entry. This was because of an increased risk of the following: (1) all-cause mortality; (2) cardiovascular mortality; and (3) total MI (fatal and nonfatal MI). Interestingly, there was no detectable difference in total stroke. To put our findings into context, for every 15 similar hypertensive ambulatory patients who have concomitant, clinically stable PAD, ≈1 patient will die over 2.7 years of follow-up.
A J-shaped relationship was observed among PAD patients and average treated blood pressure, which was most evident with systolic blood pressure. The best outcomes (lowest HRs for the primary outcome) were observed with a systolic blood pressure of 135 to 145 mm Hg and a diastolic blood pressure of 60 to 90 mm Hg. Although few data exist, recent guidelines advocate treating hypertension among patients with PAD to a goal blood pressure <130/80 mm Hg.10 Our results may challenge this recommendation; however, only a randomized trial can adequately answer this question.
A J-shaped relationship has been observed between diastolic blood pressure and adverse cardiac events; however, the existence of a J-shape curve with systolic blood pressure has been weaker.14,15 It is possible that PAD may contribute to unique vascular physiology, where such patients require higher systolic pressure to perfuse organs and prevent adverse events. Indeed, hypertension in PAD patients may be reactive and not causative in nature.
The effect of hypertensive treatment strategy among CAD patients with concomitant PAD revealed no difference on either the primary outcome or the primary outcome or first vascular procedure. However, when health-related quality of life that was poor/fair at the final visit was combined with the primary outcome, there was a modest difference favoring a calcium antagonist strategy.
It is unknown why PAD is such an adverse prognosticator, although part of the explanation may be because of inadequate treatment of traditional cardiovascular risk factors, advanced age, and more diffuse or “malignant” atherosclerosis.8,9,16,17 A recent report documented the use of guideline-recommended therapies 3 years after vascular surgery to be low; aspirin, statins, and β-blockers were used in only 50% of patients with PAD and ischemic heart disease.17 However, when guideline medications were used, they were associated with improved survival. We documented a higher frequency of aspirin, angiotensin-converting enzyme inhibitor, and sta-tin use in PAD patients at study end. Nevertheless, those with PAD had poorer prognosis versus those without PAD.
Noncontemporary studies have documented that PAD is associated with increased risk for individual cardiovascular outcomes, including death, MI, and stroke.2–5 The lack of an association with stroke in this study may be explained by insufficient power, because this was the least frequent outcome, although this finding should be considered within the context of 2 other large contemporary PAD studies.
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance Trial enrolled 12 153 patients with PAD, CAD, cerebrovascular disease, or multiple risk factors.18 Because of trial design, there was minimal overlap between these groups. In post hoc analysis, 3096 symptomatic and asymptomatic PAD patients were found to have an increased risk for individual outcomes of all-cause mortality, cardiovascular mortality, or fatal/nonfatal MI, although there was no difference in the risk of stroke.19 The Heart Outcomes Prevention Evaluation Trial enrolled 9257 patients with PAD, CAD, cerebrovascular disease (defined as previous stroke), or diabetes mellitus if associated with an additional risk factor.20 In post hoc analysis, the presence of PAD was associated with increased risk for individual outcomes of all-cause mortality, cardiovascular mortality, and MI.21 Again, there was no difference in stroke. In addition to a lack of adequate power among all of these analyses, it is possible that there may only be a weak association of lower extremity PAD with incident stroke. No insight was provided from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance and Heart Outcomes Prevention Evaluation Trial substudies on the effect of concomitant PAD and CAD on future adverse outcomes. To our knowledge, our analysis is the largest current cohort on the outcomes of patients with concomitant PAD and CAD.
The use of β-blockers in patients with PAD has been controversial because of concern of worsening lower extremity perfusion.22,23 We found no data to support the concept that a β-blocker strategy worsens lower extremity ischemia; however, this was through a secondary composite outcome that included amputations and the need for lower extremity procedures. Strengths of this patient cohort were relatively few losses to follow-up and analysis that focused on important clinical outcomes, rather than subjective limb-related events, like claudication. Current guidelines support the long-term use of β-blockers among patients with an MI, although how long patients should be treated remains controversial.24 Our results, in a cohort where one third of patients had a remote MI (>1 month before enrollment), suggest that a calcium antagonist may be a safe alternative for the treatment of hypertension among clinically stable CAD patients with PAD.
Although the diagnosis of PAD was made by site physicians using information from the patient medical charts, including history, physical examination, and diagnostic testing, this diagnosis was not uniform and objectively determined, nor was it centrally adjudicated. The type of sphygmomanometer that was used was left to site physician discretion. Since the initiation of the INVEST, the nomenclature of peripheral vascular disease, which was used on the initial case report form, has changed to PAD, because the former is too nonspecific.25 The case report form was also unable to delineate the type of peripheral vascular disease. It is possible that some of the patients in this analysis had diseases of the veins, lymphatics, cerebrovascular arteries, or muscular pain that mimicked claudication, although this is likely minimal, because these diseases are relatively uncommon, and all of these patients had another manifestation of atherosclerotic disease in the form of CAD. Alternatively, it is also possible that some asymptomatic patients with PAD were not captured. This analysis was not able to answer whether cerebrovascular, aortic, or lower extremity arterial disease portend the same prognosis, although previous analysis has documented that outcomes are variable depending on the site of disease.8
In summary, among hypertensive CAD patients, concomitant PAD carries a poor prognosis and increases the risk of major adverse cardiovascular events, including all-cause mortality, cardiovascular mortality, and MI, over a mean follow-up of 2.7 years, compared with CAD alone. PAD patients may require different blood pressure treatment goals than those without PAD. Either antihypertensive strategy among patients with concomitant PAD and CAD is reasonable; however, fewer patients assigned to a calcium antagonist strategy reported low quality of life.
Sources of Funding
The INternational VErapamil-Trandolapril STudy was funded by grants from BASF Pharma (Ludwigshafen, Germany), Abbott Laboratories (Abbott Park, IL), and the University of Florida Research Foundation and Opportunity Fund (Gainesville, FL), which ended in 2007.
R.M.C.-D. has received research grant support from Abbott Laboratories (at or more than $10 000). C.J.P. is a consultant for Abbott Laboratories (less than $10 000).