Tag: hypertension

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Hypertension Core Curriculum

The Michigan National Kidney Foundation teamed up with the Michigan Department of Community Health to create a primer on hypertension for doctors, nurses and midlevel providers. The book just was finalized. The book is not copyrighted so I am able to upload it for people to use as they see fit.

I authored the subsection on lifestyle changes and blood pressure control.

Enjoy

Hypertension Core Curriculum

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My Grand Rounds

For the last 6 weeks I have been pounding the computer finishing and perfecting my lecture which I gave at Grand Rounds at both Providence Hospital and St John’s Hospital.

I delivered the second one yesterday.

Here is the lecture with an audio track. My presentations are not self-contained most of the important data comes from me presenting. I hope you like it. (.zip file of native Keynote file)

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Articles that changed the way I practice: Sodium intake, hypertension and mortality

I have long been skeptical towards the party line that salt intake is a driver of high blood pressure, as I wrote here and here. Though hypertension is nearly unheard of in primitive cultures with sodium intake below 50 mmol/day (1.6 g day), increasing sodium intake has modest effects on blood pressure. Three mm of systolic per 100 mmol of sodium (2.3 grams) according to the Intersalt Study (PDF). This 3 mm of systolic agrees with the change in blood pressure in the DASH-Sodium trial. Similar effect size has been documented in meta-analysis:
  • A 2002 meta-analysis by Lee Hooper of 11 trials of at least 6 months duration found a 1.1/0.6 mmHg reduction from a 35 mmol (810 mg) reduction in sodium intake.
  • A broader meta-analysis published in JAMA in 1998 looked at 114 trials and found a reduction of 3.9/1.9 in hypertensive patients and 1.2/0.3 in normotensive participants.
Despite these seemingly modest results all of the clinical practice guidelines on hypertension have adopted sodium restriction as a key part of blood pressure control:
My position when talking with patients about dietary modifications for high blood pressure had been to mention sodium restriction and weight loss but focus on the DASH diet (PDF) and exercise. But this strategy has recently evolved as I became aware of a pair of studies, one by Cook et al which strengthened the sodium argument and one by Larry Appel which weakened his own DASH research.
The Rise of Sodium
The article by Nancy Cook is a follow-up on the Trial of Hypertension Prevention I and II. These were randomized controlled trials of patients with high normal blood pressure which tried to determine which lifestyle modifications were effective. Patients randomized to sodium reduction were given individual and group counseling sessions on how to reduce sodium in the diet. After 18 months the patients in the TOHP I reduced sodium intake by 44 mmol/day (1 g sodium) and blood pressure fell 1.7/0.8 mmHg. In TOHP II, after 36 months, sodium intake was reduced by 33 mmol/day (750 mg of sodium) and blood pressure fell 1.2/0.7. The decreases in blood pressure in both studies are unimpressive.
Cook went back to these studies, 10 years after TOHP I and 5 years after the completion of TOHP II, and looked at the rate of cardiovascular events (primary outcome: MI , CVA, CABG, PTCA, CV Death). They found a 25% reduction in events in patients in the low sodium group (p=0.04) that increased to 30% reduction when the study was adjusted for baseline sodium excretion and weight. These results are incredible to me, modest reductions in sodium intake that were achieved through patient education had negligible effects on blood pressure but dramatic benefits on morbidity.

The strengths of this evidence comes from two lines of reasoning:
  1. It is a randomised trial. Even though the current data comes from an observational extension of the original RCT, this does not change the fact that we are looking at two groups that were orignially randomized.
  2. This is a study which looks cardiovascular events rather than blood pressure or other intermediate outcomes.
The fall of the DASH
The DASH Trial (Appel 1997) used a diet rich in fruits and vegetables to provide increased fiber and potassium along with other trace minerals. Low-fat dairy products provide increased calcium while keeping the diet low in saturated and total fat. Participants randomized to the DASH diet were served meals with 4-5 servings of fruit, 4-5 servings of vegetables, 2-3 servings of of low fat dairy and <25%>

The results were dramatic:
  • Decreased blood pressure of 5.5/3.0 mmHg
  • Decreased in hypertensives 11.4/5.5 mmHg
  • Maximal blood pressure response occurred after only 2 weeks

The primary weakness in the DASH trials is that I’m not going to provide my patients with all of their food. It is not a clincally relevent intervention. As physicians, all we can do is educate and cousel on diet. Appel did a follow-up study where he did just that and the DASH was no longer so impressive.
The PREMIER Trial randomized patients to three groups:
  1. Control group with no interventions
  2. Standard advice: 18 face-to-face meetings to go over weight loss, and strategies to reduce sodium and alcohol consumption
  3. Standard + DASH: 18 face-to-face meetings with the same contant as the standard group with additional counseling on adopting the DASH diet
Counseling resulted in significant weight loss of 5 kg in both experimental groups versus loss of 1 kg in the control group. There was no difference in physical activity, but physical fitness did improve from baseline all three groups. They didn’t find a reduction in alcohol or sodium intake however there was good separation in the potassium intake with the greatest increase in potassium in the DASH group as would be expected. Both of the experimental groups had greater reductions in blood pressure than the control group. 40% of the patients randomized to the Standard advice and 48% of the patients in the Standard + DASH were able to lower their blood pressure below 120/80. This difference was not statistically significant.

There was no improvement in blood pressure control with the addition of the DASH diet over counseling patients on established risk factors.
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Alcohol and blood pressure: drink up?

Last week I turned in a chapter (sub-chapter?) on life-style modification for the control of blood pressure. This is part of a educational initiative for the National Kidney Foundation of Michigan.
I looked at all of the life-style recommendations in JNC-7:
I hope I will get permission to share my section on this blog because I think my conclusions differ in some important ways from the life-style dogma we hear over and over.
For now I want to share one interesting aspect: moderation of alcohol intake to reduce hypertension.
There is compelling data supporting the position that reducing or moderating alcohol intake reduces blood pressure.
One line of data comes from a recent study of two separate prospective observational trials by Sesso HD, Gaziano MJ, Et al: The Women’s Health Study (28,848 women) and the Physicians Health Study (13,455 men). They looked at initially normotensive men and women and followed them to determine the risk of developing hypertension (10.9 years of follow-up for women and 21.8 years for men) based on their exposure to alcohol. In men the risk of hypertension rose linearly with increased alcohol intake. In women, there was a J-curve, with increased risk of hypertension with teetotallers and decreased risk of hypertension until the risk that bottomed out at 5-6 drinks per week. Drinking at least one drink a day was associated with increased risk of hypertension.
Sesso’s data looks at the risk of developing hypertension, so while it provides evidence for the ill-effects of alcohol it does not answer the question of whether decreasing alcohol will ameliorate hypertension.
Xin X, et al. published a meta-analysis of 14 randomized trials of alcohol reduction in which a reduction of blood pressure was one of the end-points. Trial duration had to be at least 1 week:
Alcohol reduction reduced blood pressure to the degree promised in the JNC7 slides 3.3/2 mmHg:
What intrigued me was not the data on the reduction of blood pressure but the data on overall survival. Because the reason we care about blood pressure is because it is an intermediate outcome which is associated with cardiovascular events. If there is data on the actual outcome rather than the intermediate outcome it should by all means trump the intermediate outcome data.
Two large, high profile studies have looked at alcohol intake and survival. The biggest is a study by Thun et al and published in the New England Journal of Medicine in 1997. The data was taken from the 1.2 million American adults enrolled in the Cancer Prevention Study II and looked at 490,000 who provided complete information on smoking and drinking habits. The study showed that drinkers had a lower rate of cardiovascular disease but a higher rate of alcohol related illness. The statistics of this are interesting, a 40% reduction in the common cause of death (cardiovascular disease) ends up having much more influence than the 200-600% increase in the relatively rare deaths from conditions associated with alcohol intake:
Here is the authors description on the cardiovascular benefits of alcohol:

In contrast, the rates of death from all cardiovas-cular diseases combined were 30 to 40 percent lower among men (relative risk, 0.7; 95 percent confidence interval, 0.7 to 0.8) and women (relative risk, 0.6; 95 percent confidence interval, 0.6 to 0.7) reporting at least one drink daily than among nondrinkers. The largest reduction, in both absolute and relative terms, occurred in mortality from coronary heart disease among drinkers who, at enrollment, had reported heart disease, stroke, or some other indication of preexisting risk of cardiovascular disease.

They added a nice figure which illustrated the relative effects of smoking versus alcohol. The protective effects of alcohol are insignificant when compared to the dangers of smoking:
A second study on the mortality benefit of alcohol used the The Physicians Health Study. This is the same data that Sesso used to show the association of alcohol with the risk of hypertension. Malinski et al. looked at a cohort of subjects with pre-existing hypertension and demonstrated a 40% reduction in cardiovascular mortality with daily drinking as compared to rare or non-existent drinking. So even in the cohort that we are specifically advising to reduce alcohol intake, there is a survival benefit from drinking.
Most of my patients do not drink once a day. My feeling is that when they look at recommendations to reduce drinking they interpret that as they should stop drinking and they probably are actually increasing rather than decreasing their risk of death.
Salut
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Weight loss and blood pressure


Hmm, that’s an interesting question. When I counsel patients on controlling blood pressure I mention weight loss but don’t perseverate on it because of the general futility of of achieving lasting weight loss. Most diets deliver only modest weight loss and that weight loss is depressingly short lived:
The figure above is the primary results from a trial of various strategies to preserve weight loss. 1,685 patients were enrolled, only 1,032 lost the require 10 lbs to begin Phase 2. In Phase 2 patients were randomized to 1) minimal intervention 2) web-based interaction 3) monthly contact with an interventionist. Patients with monthly contact regained 3 lbs less than the patients with self-directed maintenance. Svetkey et al. Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA (2008) vol. 299 (10) pp. 1139-48 (PDF)

Second study looking at Weight Watchers compared to a self-help program for weight loss. Same pattern, modest weight loss followed by rebound to regain much of the lost weight. Heshka et al. Weight loss with self-help compared with a structured commercial program: a randomized trial. JAMA (2003) vol. 289 (14) pp. 1792-8 (PDF)

I focus my limited office time on changing patients’ diet to reduce blood pressure. I recommend the DASH diet (PDF) to all of my patients without significant metabolic bone disease or hyperkalemia because I believe the data shows that it is the most effective life-style intervention to ameliorate hypertension. Unfortunately those two exclusions (bone disease and potassium) exclude many of my patients. I usually don’t recommend the low sodium version of of DASH because I feel that the reduction in palatability is not supported by the rather modest additive effects (an additional 3 mmHg reduction in SBP). Most of my patients recognize that they eat too much and have been trying to reduce calories, and lose weight for years prior to seeing me. I feel that by discussing the DASH diet and not rehashing the same tired dietary advice that every doctor has been promoting, I provide them with a novel view of dietary changes that they are willing to try.

Still, I think The Kidney Group has an interesting question, what is more important weight loss or diet changes?

NephSAP recently reviewed hypertension. On page 98 they had this table which compared various lifestyle interventions and their effect on blood pressure:
Unfortunately they grouped diet and weight loss in one group so it does not allow me to separate out the effect of changing diet from changing weight. Regardless, the effect on blood pressure looks modest compared to the findings of the DASH diet or DASH sodium intervention. From the abstract of the DASH-Sodium trial (PDF):

As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension.

The Archive published this meta-analysis (PDF) in 2008 looking at weight loss by diet or drugs with respect to mortality and blood pressure control.


They found that weight loss did result in blood pressure reductions but the reduction was modest. Additionally not all methods were equal, with silbutamide (Meridia) resulting in an increase in blood pressure despite being effective at reducing weight. They were unable to find any studies which showed a reduction in weight reducing mortality.

The above systemic review mentioned that the TONE study was one that was particularly well done. The TONE trial (PDF) was published in JAMA in 1998 and compared sodium restriction to weight loss to usual care in a two by two factorial design. The enrolled 585 obese patients to be randomized to either weight loss, no weight loss, salt restriction or not. Another 390 were randomized to either salt restriction or usual diet.
The investigators achieved nice separation of the groups with regard to weight loss. The study began with every patient weaning off their antihypertensive medication and the primary end-point was the fraction resuming their pharmacologic blood pressure medications and the time to resumption. Weight loss was more effective than no intervention and about equally efficacious as sodium restriction:

Note the lower starting blood pressure for sodium intake, this accounts for some of the difference in the effect on blood pressure.

Though TONE showed no difference between weight loss and sodium restriction, I feel that diet is probably more important because sodium restrictionis not the most effective dietary change to reduce blood pressure, the DASH diet is. I feel that if the TONE trial was rerun with the DASH diet replacing sodium restriction we might see that diet is more important than weight loss.

One thing I am doing in my clinic more and more is recommending bariatric surgery. Medical and behavioral changes have a poor track record at providing lasting and significant weight loss. Bariatric surgery shows lasting weight loss 10 years out and it allows patients to recover from hypertension and diabetes. Sjöström et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med (2004) vol. 351 (26) pp. 2683-93. (PDF)

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Is hypertension in octagenarians a characteristic or a disease

I was at the NKF Spring Clinical meeting and I saw variations of the two following slides in at least three different lectures:

The slide on the left comes from the AHA Heart Disease and Stroke Statistics from 2007 (PDF). It shows the increasing prevalence of hypertension as people get older. The slide on the right is from the Framingham Heart Study (PDF) and shows the 20 year risk for normotensive adults for developing hypertension. Both figures are repeated below:


The part of these figures that kept gnawing at my brain was putting them together, stacking them if you will. 60-70% of the sixty-year olds have hypertension and the minority that are normotensive have a 90% chance of developing hypertension by the time they are 85. So essentially every 80 year old has hypertension.

Does hypertension cease to be a disease when everybody has it? Is hypertension less pathology and rather part of the normal physiology of aging?

Speaking against the idea of geriatric hypertension being normal physiology is the powerful survival advantage gained by treating the high blood pressure. This data comes from HYVET published last spring in the NEJM (PDF). Prior to HYVET there was retrospective data pointing to better survival with higher blood pressures (Oates 2007) and a meta-analysis of 80+ year olds enrolled in RCTs showed a reduction in cardiovascular evens but a trend to increased total mortality.

The HYVET ransdomized 3,845 octagenarians with blood pressures 160-190 with a diastolic of less than 110 to either placebo or indapamide (thiazide-like diuretic) with additional perindopril if the systolic blood pressure remained over 150. The primary end-point was number of strokes (fatal + non-fatal)

Results. The investigators achieved good blood pressure separation between the control and experimental groups with a 15 mmHg difference in the systolics and 6 mmHg difference between the diastolics.

The effect on morbidity and mortality were dramatic (all results expressed as intension-to-treat) with active treament resulting in:

  • 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], –1 to 51; P=0.06)
  • 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05)
  • 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02)
  • 23% reduction in the rate of death from cardiovascular causes (95% CI, –1 to 40; P=0.06)
  • 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001)
  • Fewer serious adverse events (358, vs. 448 in the placebo group; P=0.001).
Click on the graphs to see larger versions.

So even if hypertension in the elderly is not a disease, treating it seems to have dramatic benefits for patients. Vote your opinion!

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Its not the sodium intake its the sodium:potassium ratio

Don’t worry only about sodium intake (NYC, I’m looking at you) and its not just potassium intake (DASH diet in the cross-hairs). It’s all about the sodium potassium ratio. This is shown by Cook et al (PDF). during reanalysis of the Trial of Hypertension Prevention I and II. This trial had serial 24-hour urine collections done in 2,275 patients with pre-hypertension in the late 80’s and 90’s. The investigators looked at that data through the lens of 15 years of follow-up to determine the risk of cadiovascular events:

In observational analyses of the mean urinary excretion during 11⁄2 to 3 years, we found a suggested positive relationship of urinary sodium excretion and a suggested inverse relationship of urinary potassium excretion with risk of CVD, but neither was statistically significant when considered separately. Both measures strengthened when modeled jointly, with opposite but similar effects on risk. However, the sodium to potassium excretion ratio displayed the strongest and statistically significant association, with a 24% increase in risk per unit of the ratio that was similar for CHD and stroke and was consistent across subgroups.

Here is the key figure. Note in the graph the rate of events is presented on a log scale so the 2 indicates a rate 100 times the rate at zero.

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Statins fail again

Statins have a tortured relationship with nephrology. Our patients have accelerated atherosclerosis and they die overwhelmingly of cardiovascular disease. So one of my primary jobs is to continually optimize cardiovascular risk factors to save my patients

Control blood pressure, start an aspirin, and maximize the statin are the lather, rinse, repeat of my world.

That said we have little data that this makes a whit of difference, at least in our dialysis patients.

Aspirin

  • No randomized trials have been done on the role of aspirin to prevent cardiovascular events among dialysis patients.
  • Aspirin was found to increase acute coronary syndrome in an unbadjusted analysis but was not significant in multivariate analysis.
  • Berger et al. (PDF), however found a dramatic reduction in 30-day mortality for patients with acute myocardial infarction given aspirin. Unfortunatly fewer dialysis patients received ASA and other standards of heart-attack care (beta-blocker and ACEi) than patients not on dialysis.
The survival of patients based on whether they received ASA for their acute MIThe use of standard therapies for acute myocardial infarction was lower among dialysis patients, even patients deemed ideal candidates for the therapy.


Blood pressure

  • Hypertension, along with cholesterol and obesity, is subject to reverse epidemiology in dialysis patients. This means that observed epidemiology trends are the opposite of what you would expect from data on non-dialysis patients. Lower blood pressure leads to high mortality, lower cholesterol leads to higher mortality, increased BMI yields better observed survival. The observational data, however, does not mean that interventions to lower blood pressure will lead to the same bad outcomes.
  • A recent meta-analysis (PDF) of 8 randomized trials of anti-hypertensive therapy gives credence to the practice of treating hypertension in dialysis patients.

  • One thing high lighted by the trial, though, is the paucity of evidence for this treatment: They were able to find only 1,679 patients. Terrible.

Statins

  • The 4D study is one of the few randomized controlled trials in dialysis patients and unfortunately did not show any improvement in mortality with atorvastatin. The study randomized 1,255 hemodialysis patients to either 20 mg of atorvastatin or placebo. After 4 years they found the statin was safe and effective in reducing the median serum LDL cholesterol level by 42%. However, the primary endpoint—cardiac death, nonfatal MI, and stroke—was reduced by insignificant 8% (P=0.37).

  • The authors found a significant increase in fatal strokes among the patients randomized to atorvastatin. (RR 2.03, P=0.04).
  • Today came word that another randomized controlled trial on statins among hemodialysis patients, AURORA, was also a bust. Published yesterday in The Journal, AURORA randomized 2,776 dialysis patients to 10 mg of rosuvastatin (Crestor) or matching placebo. The end-point was a composite of CV death, non-fatal MI, and non-fatal stroke. Average follow-up was 3.8 years and there was no difference in the primary outcome (396 outcomes with rosuvastatin versus 408 on placebo, P=0.51).

  • AURORA found no increased risk of strokes as found in the 4D study.
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Journal Club: Dry weight adjustment in dialysis

Agarwal continues his streak of important studies on blood pressure in dialysis patients. This study shows that reducing the dry weight results in reductions in ambulatory blood pressures done between dialysis sessions. Agarwal had previously demonstrated that in-center blood pressure readings poorly correlated with ambulatory blood pressure. One of the key findings was that the systolic fell twice as much as the dialtolic blood pressure. This means they did not only reduce the blood pressure but they also reduced the pulse pressure, something which we really are unable to do with antihypertensive drug therapy (which reduces both the systolic and diastolic blod pressure and have little affect on the pulse pressure).

Personal note: Agarwal was one of my attendings when I was a resident and wrote one of my letters of recommendation for fellowship.